After Steve shows a lack of interest in Stan's job, Stan replaces him with Barry, Steve's malicious friend. Barry frames Steve to eliminate him from the household, but when Steve discovers Barry's weakness, he relies on his CIA skills to save the family. Meanwhile, Roger takes an impressive keg-stand and uses it to become a fraternity brother.
Peter wants to top Joe, who just built a new home theater system, so he starts to build a multiplex in his backyard. In doing so, he discovers an Indian burial ground. He finds an Indian chief's skull and the Griffin house becomes haunted. Stewie gets sucked into the television and strange events follow as they try to get Stewie back from the poltergeist.
The staff attends to an intern from another hospital who has short-term memory loss. This intern, named Marshall, also has caused a car accident that involved a married couple, their unborn baby and the woman's parents who the staff are also treating. The pregnant woman is named Melanie and she will die but her baby may survive. One of the female interns meets up with a woman from her past who is planning on having a family of her own. Cristina is in a good mood although Alex, Izzie, George, and Meredith are having problems but in the meantime Burke hasn't forgiven Cristina for her late night faux pas. Meredith and Izzie are making fun of Callie's household habits and George and Callie are having a fight because of George's roommates. Addison is continuing to own Alex and he's upset about it. Denny has an outburst at Izzie and Derek has an outburst at Meredith.
Marge goes on a cleaning frenzy before the housekeeper she’s won the services of comes to the house. One spot remains and she mixes a number of toxic cleaners together to tackle the job. The noxious mixture knocks her out and she wakes up suffering from amnesia. Marge is taken home and the family tries to bring back her memory. She starts to get back memories of her children and other insignificant things, but when it comes to remembering her husband, nothing he does seems to jog her memory. When he can’t get her to remember him, he tries to win her all over again, especially after Patty and Selma get her back out on the dating scene.
Jeremy tests the Koenigsegg CCX and Stig is doing his best to kill himself in it. James drives the new Honda Civic and Richard is relegated to driving a most embarrassing convertible: the Nissan micra C+C. The Renault Espace is turned into the world's first convertible people carrier by having its roof sawn off.