After wrestling on the independent circuit for years as Alexis Laree, Mickie Laree James was signed to a developmental contract by World Wrestling Entertainment in October 2003. In October 2005 she was promoted to the main roster and assigned to the RAW brand.

Mickie James made her professional debut in the summer of 1999 as a ring valet for KYDA Pro Wrestling in Manassas, Virginia. She started out managing some of the most popular stars in the promotion such as Steve Corino and Tommy Dreamer, but eventually found herself being drawn into feuds with other wrestlers and their valets and managers. Eventually James chose to step into the ring as a wrestler herself.

James's career has gone through many promotions. In late 1999 she expanded out to other promotions including all-female promotions Beautiful Babes of Wrestling (BBOW) and Professional Girl Wrestling Association (PGWA). She probably made her largest impact wrestling for Maryland Championship Wrestling, where she engaged in several long-running feuds.

In January 2001 James made her debut appearance for two new women's promotions, Dangerous Women of Wrestling (DWOW) and Women's Extreme Wrestling (WEW). Both promotions worked together to promote women's wrestling with a hardcore edge, and WEW had regular monthly pay-per-view matches. James's feuds from here include matches against "Prime Time" Amy Lee, Dee-Dee Venturi, a re-ignition of her feud with Candie from MCW, and the start of a new series of feuds with "Simply Luscious" Ronnie Stephens. Her matches against Stephens stretched to many independent promotions in the northeast.

On March 26, 2003 James appeared on a NWA:TNA PPV. Although she was on NWA:TNA's first-ever PPV in late 2002 as part of the all-women's lingerie battle royal, her arrival in 2003 marked the first time she was highlighted, as she helped out The Amazing Red in a mixed tag-team match against Kid Kash and valet Trinity.

On August 18, 2003 James was offered a developmental contract with World Wrestling Entertainment. She was immediately replaced on the next NWA-TNA PPV by CM Punk, who had been feuding against Raven but had recently won his respect after Punk beat Raven in a Dog Collar Match weeks earlier.

James made her debut on the October 10, 2005 episode of WWE RAW under her real name, and was billed as an obsessed fan of Trish Stratus coming to her rescue following an attack on Stratus by Victoria. A similar storyline featuring Tori and then-WWF Women's Champion Sable took place in 1998 and 1999. It's been implied that James was put on the active WWE roster long after she should've been. On the October 17, 2005 episode of RAW, James competed in her first WWE-televised match, a tag match with Ashley Massaro and Stratus against Victoria, Candice Michelle and Torrie Wilson which ended when Victoria pinned James. James took part in a "Fulfill Your Fantasy" Diva battle royal for the WWE Women's Championship at Taboo Tuesday 2005, ensuring that Stratus would retain her title by sacrificing herself in order to eliminate Victoria. On the December 12, 2005 edition RAW Mickie James defeated Victoria to receive a match against Stratus for the WWE Women's Championship at New Years Revolution.

On the December 26, 2005 edition of "RAW" Mickie James shared an 'intimate' kiss with Trish Stratus under a mistletoe. The surprised Stratus, in disbelief, ran from the situation, stressing out James. During the next "RAW", James would go as far as standing outside Trish's shower complimenting on her "nice boobs".

Into the beginning of 2006, James continued to be involved in the lesbian crush angle with Stratus. During New Year's Revolution on January 8, James lost to Stratus in a match for the WWE Women's Championship. During a post-match interview, Mickie claimed it "felt like silk" when her skin touched Stratus's.

Following Stratus's Women's Championship match victory over Candice Michelle on February 27, James attempted to hug Stratus while on her knees. Trish wanted nothing to do with this attempted lesbian sex act and pushed Mickie away. The situation grew to a head on March 6, when Mickie began hosting a segment called "Kiss Cam," where she licked the cover of the newly issued "WWE Divas" magazine – specifically, a cover photograph of a lingerie-clad Stratus.

Trish Stratus finally had enough and confronted Mickie James in the locker room. She told James that her obvious crush was "too much" and asked that they "maintain their space." James was obviously stunned and hurt by Stratus's comments.

Mickie James using Trish Stratus's "Stratusfaction" at Saturday Night's Main Event, completing her heel change. Mickie James would finally become a fully fledged heel, just after teaming with Trish Stratus against Victoria and Candice Michelle at WWE Saturday Night's Main Event on March 18.

In March 2006 Trish Stratus and James were victorious at Saturday Night's Main Event, and after the match Mickie James led Trish Stratus to believe that she was okay with their parting ways after the match and offered a handshake. Stratus shook her hand, but Mickie went in for a kiss (which caused Trish to turn her head so that it landed on the cheek) and a hug. Stratus pushed her off, but James then attacked Trish Stratus with a Chick Kick followed by a Stratusfaction completing her heel turn. In an interview after the attack on Trish, James stated several times, "Do you love me now, Trish?!". She later stated in an interview on WWE.com Unlimited that since Stratus broke her heart, now she was going to break Stratus.

On RAW the next Monday, James kidnapped Ashley and used her to lure Stratus out to the ring. Stratus attacked James and started untying Ashley, but Mickie caught up with Trish and knocked her out with a Tornado DDT. After doing so, she proceeded to ask the unconscious Stratus, "Do you love me now Trish?" and kissed her.

On March 27 Mickie James had one last mind game to play with Trish Stratus. Mickie James was in her room, with many photos and pictures of Stratus and candles around her. She said "I admired Trish for so long" and that at WrestleMania she had two goals, to take the WWE Women's Championship and also to see Trish's destruction. At WrestleMania 22, James defeated Trish Stratus following a Chick Kick. James, who despite being heel was cheered during the match, became the first Diva to win the Women's Championship on her WrestleMania debut.

The next night, Trish Stratus and Torrie Wilson were set to face Candice Michelle and Mickie James. When James came down to the ring, she had her hair dyed blonde, wearing Stratus's wrestling outfit and came down to the ring with a theme music that began like Stratus's own. The following week, on the April 10 edition of RAW, a role reversal was seen as Stratus came out to the ring dressed in James's old attire, complete with brunette hair.

An angle was created between Mickie and Melina, in January 2007 when Melina became the number one contender for the Women's Title. Following a successful title defense Mickie teamed with Super Crazy in a mixed tag team match against Melina and Johnny Nitro. After Melina pinned her for the victory, she challenged Mickie to a rematch for the title. Mickie dropped the Women's Championship to Melina on February 19 and failed to regain the title during the first ever Women's Falls Count Anywhere match in WWE history.

The feud between Mickie and Melina continued at a house show in Paris, France on April 24, Mickie won her 3rd Women's Championship during a Triple Threat Match that also involved Victoria. However, since she pinned Victoria and not Melina, Jonathan Coachman announced that a rematch would take place immediately. Mickie lost the match and the title went right back to Melina, giving her the shortest Women’s Championship reign in WWE history.

On the April 14, 2008 edition of Raw, held in London, James defeated Beth Phoenix to win her 4th Women's Championship Title. James re-entered into a feud against Beth Phoenix in mid-2008 where she and Kofi Kingston teamed up against Phoenix and Santino Marella. At SummerSlam in a Winner Take All tag team match for both the Women's and Intercontinental Championships, James and Kingston lost their titles to Phoenix and Marella. After James lost her Women's Championship, she had two rematches for the championship but was unsuccessful in regaining the title.

Following an appearance in the 25-Diva battle royal at WrestleMania XXV in April 2009, James began feuding with WWE Divas Champion Maryse going into Night of Champions on July 26, 2009. At the event, James defeated Maryse to win her first Divas Championship, becoming only the second Diva in history to have held both the Women's and Divas titles. James dropped the belt to Jillian Hall after an approximate three month title reign in October. After the show, James was moved to the SmackDown brand for the first time in her career due to a Diva trade made by Raw guest host Nancy O'Dell.

James made her SmackDown debut on October 23 by defeating Layla. The next week, a controversial angle began that saw Team Lay-Cool bully James, resulting in a five-on-five elimination tag team match at the November pay-per-view event Survivor Series, where James' team prevailed over WWE Women's Champion Michelle McCool's team. On the December 3 edition of SmackDown, James became the number one contender for McCool's title by defeating Beth Phoenix and Natalya in a triple threat match. The following week, James challenged McCool for the Women's Championship at TLC: Tables, Ladders & Chairs, but was unsuccessful after interference from Layla. The storyline feud continued into the Royal Rumble on January 31, 2010 where James finally defeated McCool to win her fifth Women's Championship. Over the next couple of weeks, SmackDown consultant Vickie Guerrero was introduced into the rivalry, choosing to side with Team Lay-Cool after James accidentally doused her with cottage cheese. On the February 26 edition of SmackDown, McCool used her rematch clause to face James for the Women's Championship, with Guerrero acting as special guest referee. After Guerrero slapped James in the face, McCool pinned her to regain the title.

On March 9, 2010 WWE.com announced that James was diagnosed with a staph infection on her right knee. She returned on the March 22 edition of Raw, where alongside Kelly Kelly, she accompanied Eve Torres, Beth Phoenix and Gail Kim in their losing effort against Michelle McCool, Maryse and Layla, who had Vickie Guerrero and Alicia Fox in their corner. This set up a 10-Diva tag team match at WrestleMania XXVI in which James made an unsuccessful in-ring return after Guerrero pinned Kelly following a "hog" splash. James' final match in WWE was aired on the April 23 edition of SmackDown, teaming with former rival Beth Phoenix against Team Lay-Cool in a losing effort. She was released from WWE one day earlier on April 22.