Vickie later reappeared at SummerSlam to convince Eddie to put a stop to his war with Mysterio and not to go through with the "Custody of Dominik" ladder match that night.

[6] On November 13, 2005, Eddie Guerrero died of heart failure in his Minneapolis hotel room and was found by his nephew Chavo.

[7] On-screen, this led to Rey Mysterio, Eddie's real-life friend, getting more screen time and higher profile matches, including defeating Kurt Angle and Randy Orton at WrestleMania 22 for the World Heavyweight Championship.

[8] The night before WrestleMania, Eddie was posthumously inducted into the WWE Hall of Fame, and Vickie accepted the honor on his behalf.

[9] Vickie later openly sided with Chavo and hit Mysterio in the back with a chair on the following SmackDown!, turning heel in the process.

[10] On the September 1 SmackDown!, the evil Vickie declared herself Chavo's business manager and Mysterio an "insignificant chapter" in her past.

[15] He tried to figure out what Vickie was doing with Eddie's estate while also defending the WWE United States Championship in a rivalry with Chavo.

[19] During her work as General Manager, she had a storyline where she had a romantic relationship with Edge, giving him chances for the World Heavyweight Championship.

[11] In early 2008, she formed La Familia with her nephew Chavo, Edge, the team of Curt Hawkins and Zack Ryder, and later, Bam Neely.

[22] The storyline continued at The Great American Bash, where Triple H retained the title after Edge performed the Spear on Guerrero.

[26] On the following Raw, Guerrero announced that Edge would be facing Big Show for his World Heavyweight Championship at WrestleMania 25.

On the March 9 episode of Raw, John Cena showed footage of Vickie cheating on Edge with Big Show after Guerrero had added Cena to the World Heavyweight Title match through blackmail of revealing the secret affair, making it a triple threat in the process.

[27] On June 7 at the Extreme Rules pay-per-view, Vickie lost the "Miss WrestleMania" crown to Santina in a hog pen match with Chavo by her side.

After her announcement, Edge came out and told Vickie that he was sorry for saying disrespectful things about her, only to reveal that he only married her so she could help him in World Championship matches, and now that she quit, she was useless to him in his endeavors to become the champion again.

[29] The following week after Escobar failed to capture the Intercontinental title from John Morrison, Vickie ended their relationship.

Escobar claimed that he could not take it any longer, saying he only went out with her for power, mirroring what Edge admitted as to why he had married Vickie on the June 8 episode of Raw.

After the match, McCool and Layla began to beat down Tiffany until Beth Phoenix made the save, in the process delivering a clothesline to Vickie.

Two weeks later Guerrero appeared in a 5-on-1 handicap match with Alicia Fox, Maryse and Team LayCool against Beth Phoenix.

[35] Although not the general manager, she returned to SmackDown as the Consultant on the May 14 episode and forced Phoenix to face Team LayCool in a handicap match, which Layla won to achieve her first WWE Women's Championship.

On the February 4 episode of SmackDown, Ziggler and LayCool lost to Edge and Kelly in a two-on-three handicapped mix tag match for the World Heavyweight Championship.

On the March 7 episode of Raw, Guerrero and Ziggler made their return to the brand, with Vickie managing him in a singles match defeating John Morrison.

The general manager then continued by issuing a match between her and Trish Stratus for the following week, with the stipulation being if Vickie wins, she would be hired.

[39] At the Capitol Punishment pay-per-view, Ziggler won the United States Championship from Kofi Kingston, with the help of Guerrero.

[42] On the June 18 episode of Raw, Vickie ended her clientele service with Jack Swagger and renewed her romantic relationship with Ziggler.

On the December 10 episode of Raw, Guerrero defeated AJ Lee with help from Brad Maddox, who was the special referee for the match.

The following night on Raw, Guerrero teamed with Cena to defeat the new couple of Ziggler and AJ by disqualification due to interference from Big E Langston.

[44] On June 23 episode of Raw, Guerrero lost in a pudding match against Stephanie McMahon with her job on the line, after interference by Alicia Fox, Layla and Rosa Mendes.

She was then fired as general manager of both shows, but got her retribution over McMahon by throwing her into the mud pool and mouthed, "I love you," a tribute to her late husband, Eddie Guerrero, and performed his signature taunt while leaving the stage.

[45] On the July 4, 2016 episode of Raw, Vickie returned during a segments where she wanted to become the new "SmackDown Chief Operating Officer" after the WWE Brand Extension.

[53] Guerrero's approach to her work as manager is "to make them shine and do my little part and just be there at the right moment and the right time to do the right thing" while "my role is just an embellishment of the superstar that’s in the ring.