Francine Smith is complicated woman. She has spent the entire run of American Dad trying to keep Stan from going too far off the deep end, as well as keeping Roger well stocked with wigs and booze. Francine is also her own person who had a wild life before she met Stan, and that includes an ongoing feud with George Clooney.
When Francine was a lot younger, she had a dream of becoming an actor. She even got her big break on a TV show playing a front desk agent at a hotel. It should have been the moment that launched her career, but she was upstaged by a young Clooney, and the rest was history. He went on to become a world famous actor, and Francine's dreams faded away. While she's happy with her life, what could have been nagged at her, and her birthday seemed to be a trigger.
While Season 1, Episode 23, "Tears of a Clooney," was the first episode where she openly discussed her hatred of George Clooney, this wasn't the first time he had come up. Francine was known to make snide remarks about Clooney on occasion beforehand, and it was easy to write those moments off as American Dad's usual random shots at celebrities. Instead, it was something much deeper.
After Francine revealed the truth to Stan on her 39th birthday, he decided to do something about it. Putting all of his CIA training, resources and connections to good use, Stan formed a crack team to take Clooney down. They formulated a two-pronged plan. First, Stan would become part of Clooney's posse, acting as their inside man. While that was happening, Francine would train to become Clooney's ideal woman, make him fall in love with her and then break his heart.
The hitch in the plan became Stan. He fell for Clooney as they became each other's best friends. He warned Clooney about the plan, sabotaging the whole operation. At one point, he even handcuffed Francine to prevent her from trying to go after Clooney. Francine actually cut her own hand off so she could continue her path of vengeance, deciding to just kill the actor.
In the end, Francine chose to let the whole thing go and went home with Stan, but he gave Francine some semblance of closure by breaking up with Clooney as his best friend, leaving the actor a distraught mess. While this move also hurt Stan incredibly, his love of Francine trumped his love of Clooney.
Obsessively chasing Clooney wasn't even craziest part of this whole mess. Francine and Stan's war on Clooney started on her 39th birthday, and it ended on her 40th birthday, meaning they were away from their kids and their home for an entire year. During that time, Hayley fended off a mysterious illness while Steve and Roger used foster children to run an illegal winery in the backyard. Francine probably should have learned to let things go a lot sooner, if only to help those poor children.