After a series of reunions during the 1990s, Wiedlin, Carlisle, Caffey, Schock and Valentine reunited in 2000 to record God Bless the Go-Go's (originally titled Vision of Nowness), their first studio album in 17 years. The album's title and concept came from Wiedlin.
In 2000, Wiedlin sang in Frasier episode "They're Playing Our Song". In 2001, she had a regular role in MTV's Spyder Games, portraying the "ex-rock chick who runs the local coffee house" where the characters hang out.