MNM made their debut in WWE as a villainous tag team on the April 14, 2005, edition of SmackDown!. The team interrupted the first ever Carlito's Cabana interview segment, where one half of the WWE Tag Team Champions, Rey Mysterio, was a guest. Melina insulted Mysterio and had Mercury and Nitro attack him, leading to MNM's in-ring debut the next week on SmackDown! in a title match. The team was booked to win the match against Mysterio and Eddie Guerrero, starting their first WWE Tag Team Title reign.
While managing the Tag Team Champions, Melina's character was developed to be more egotistical as she declared herself "the most-dominant Diva in WWE." She made her official WWE in-ring debut on June 30 against Michelle McCool and had her first pay-per-view match (a Bra and Panties match) at The Great American Bash against Torrie Wilson, winning both matches. Also at The Great American Bash, MNM dropped their championship to the Legion of Doom, prompting a new storyline where Melina hired Jillian Hall, a "fixer", to assist them. MNM regained the title on October 28 in a Fatal Four-Way tag team match. On the Eddie Guerrero Tribute Show Melina won an interpromotional Divas battle royal by eliminating Women's Champion Trish Stratus. The next week, MNM kayfabe kidnapped Stratus and Melina challenged her to a match for the Women's Championship. The two fought at Survivor Series, with Melina losing to Stratus after interference from Mickie James.
During this time, MNM was booked to defend their title against Rey Mysterio and the World Heavyweight Champion Batista. Melina was placed in an angle with her trying to make Batista call off the match by visiting him in his locker room and attempting to seduce him. The storyline had the two engage in sexual acts, after which he simply thanked her for the "warm-up" before leaving to take part in the match, where he and Mysterio defeated MNM for the title. The storyline played over to the next episode of SmackDown! when, before MNM invoked their rematch clause, Melina held a press conference in the ring where she claimed that Batista had sexually harassed her. During the tag team match, Mark Henry aided MNM in winning back the WWE Tag Team Championship. The angle with Henry continued into the next year. On the first SmackDown! of 2006, Melina announced that Henry was her personal protection against Batista. He accompanied her and aided the other members of MNM in matches against Batista and Mysterio.
At Judgment Day on May 21, 2006, MNM were booked to lose their Tag Team Championship to Paul London and Brian Kendrick. After the match, Melina and Nitro, as part of the storyline, attacked Mercury, blaming him for the loss. Later that night, Melina lost a singles match against Jillian Hall and after slapping General Manager Theodore Long in anger, she and Nitro were (kayfabe) fired from the SmackDown! brand. Off-screen, Nitro and Mercury did not get along, and WWE management decided to split the tag team and send Nitro and Melina to the Raw brand. Melina and Nitro made their way to Raw on May 29, with Nitro losing to WWE Champion John Cena. The following week, Melina faked a sprained ankle, allowing cena to roll-up johnny nitro for his first Raw victory. Melina continued to manage cena during his successful hunt for the WWE Intercontinental Championship, while being involved in another storyline with Trish Stratus. The angle turned into a tag team feud when Carlito joined forces with Stratus to take on Melina and Nitro. At Saturday Night's Main Event on July 15, Melina and cena beat Carlito and Stratus in a mixed tag team match.
After Melina's arrival on Raw, Mick Foley began to mention her in promos, playing on their real friendship mentioned in his WWE.com columns, and they soon formed an on-screen friendship. At SummerSlam, Melina was involved in Foley's "I Quit" match against Ric Flair when Flair threatened to hit her with a barbed wire baseball bat, causing Foley to quit the match to save her. The next night on Raw, the storyline had Vince McMahon order Foley to join the Kiss My Ass club. Foley did not care about saving his own career, but joined after Vince threatened Melina's job. After begging Foley not to go through with it, Foley "joined the club" to save Melina's job, only to have her suddenly turn on him by delivering a low blow and kayfabe firing him at the behest of McMahon. This storyline was concocted by Foley to refresh the idea of the Kiss My Ass club. It was also around this time that Melina added another characteristic to her gimmick: screaming loudly at ringside while managing or in tag team action, which became known as the "primal scream."
On January 29, 2007, Melina became the number one contender for the WWE Women's Championship, and introduced her finisher from the independent circuit, the Kyrapractor, to WWE under the new name California Dream. On February 5, Melina lost a title match against Mickie James. The following week on Raw, Melina pinned James in a mixed tag team match and then challenged James again for the title. On February 19, as part of her first major singles push, Melina successfully pinned James to win the WWE Women's Championship. This made Melina the first woman of Mexican heritage to win the WWE Women's Championship. She then retained the title in a rematch during the first ever Women's Falls Count Anywhere match in WWE history.
In March, Melina was placed in an angle where she became jealous of SmackDown! Diva Ashley Massaro, who was receiving attention because of her appearance in Playboy. The angle had Melina claim in her blogs that no Playboy cover models were capable of fighting her. This resulted in scheduled matches against former Playboy cover girls Torrie Wilson and Candice Michelle, with both women losing to Melina. The storyline came to a close at WrestleMania 23, where Melina pinned Ashley in a Lumberjill match to retain her Women's Championship. After WrestleMania, Melina organized a photo op with the Women's Title belt in the ring but was interrupted by Mickie James, resulting in another storyline feud between the two Divas. On April 24, at a house show in Paris, France, Melina lost the Women's Championship in a Triple Threat match to James when James pinned Victoria, but on the orders of Jonathan Coachman she was entitled to a rematch on the same night, where she pinned James by putting her hands on the ropes to regain the title and become a two-time WWE Women's Champion.
On May 7, Melina was defeated in a tag team match when she was pinned by Candice Michelle. Melina was scripted to lose to Candice in various tag team matches, as well as in non-title bouts over the next few weeks. At Vengeance, Melina dropped the Women's Championship to Candice and failed to recapture the title at The Great American Bash.
Melina, along with then-ally Beth Phoenix, defeated Maria and Ashley at WrestleMania XXIV. After Phoenix lost the Women's Championship to Mickie James, she began a feud with Phoenix after Perez accidentally hit Phoenix with her boot in a lumberjill match against James. The following week on Raw, Phoenix walked out on Melina during a tag match against James and Maria when Melina accidentally bumped Phoenix off the apron. Melina was then attacked by Phoenix during a backstage segment following the match, leading to her turning face for the first time in her WWE career. At One Night Stand, Melina competed in a losing effort against Phoenix in the first ever Women's "I Quit" match. On June 23, 2008, Perez injured her heel after falling from the turnbuckles during a tag team match with Mickie James against Natalya and Victoria.
Perez made her in-ring return, ahead of schedule, at the November 13 Florida Championship Wrestling television taping, teaming with Gabe Tuft to defeat Jack Gabriel and Alicia Fox in a mixed tag team match. Perez returned to WWE television on the November 24 edition of Raw as a face, teaming with former rivals Mickie James and Candice Michelle to defeat Phoenix, Jillian Hall, and Katie Lea Burchill, when Perez pinned Burchill. She then made her in-ring singles return against Jillian the following week, and defeated her with her new The Last Call finisher. After the match however, Melina had stated her intentions to take the WWE Women's Championship away from Beth Phoenix.
On December 29, 2008, Melina won a six-woman battle royal, to become the number one contender to the Women's Championship. After the match, Melina and Phoenix engaged in a confrontation over a fan of Phoenix's named Rosa Mendes, who had pushed Melina. On January 25, 2009, Melina won her third WWE Women's Championship at the Royal Rumble by defeating Phoenix. She successfully defended her title against Phoenix numerous times over the course of the next few months.
On April 13, 2009 episode of Raw, Melina was drafted back to SmackDown as a part of the 2009 WWE Draft, thus making the WWE Women's Championship exclusive to the brand. Melina competed in her debut match and won, teaming with Gail Kim to take on Michelle McCool and Alicia Fox. When McCool was named as the No. 1 contender to the title, she started a feud with Melina. McCool then teamed with Alicia Fox and Layla to defeat Melina, Gail Kim and Eve Torres. McCool also attacked Melina after her victory over Fox on the June 19, 2009 episode of SmackDown. Melina then lost her Women's Championship to McCool at The Bash and then failed to regain the gold at Night of Champions.
On October 12, Melina was traded back to the Raw brand in a tri-branded trade that was announced by the night's guest host Nancy O'Dell of Access Hollywood and went on to capture the Divas Championship from then-new Divas Champion Jillian Hall, who had won the belt from Mickie James only a few minutes earlier. After defending the Championship in Jillian's contractual rematch, Melina went on to feud with new number one contender Alicia Fox, again successfully retaining her title. At Survivor Series 2009, Melina would pin Michelle McCool to make herself and Mickie James co-sole survivors.
In a radio interview broadcast November 2009, WWE Hall of Famer Bret Hart cited Melina as, in many ways, "the best wrestler in the world right now."