He is half of the long-standing Brooklyn, New York–based alternative rock duo They Might Be Giants with John Linnell, for which he writes, sings, and plays rhythm guitar.

Her father, Brigadier General Ralph Hospital, was an artillery commander in the U.S. Army in the Italian Campaign during World War II.

In the 2002 documentary Gigantic (A Tale of Two Johns), he was described as holding a leadership role in the group, managing most details of their live act and handling much of the promotion effort.

As a songwriter, Flansburgh enjoys a mix of styles; many of his songs have an absurdist and satirical bent, but he often breaks for more earnest and romantic themes as well.

He penned and performed vocals on the group's first Grammy Award-winning effort, "Boss of Me", which charted in Europe and served as theme song to the hit television series Malcolm in the Middle.

[7] Flansburgh has also directed music videos for such artists as Soul Coughing, Ben Folds Five, Frank Black and the Catholics, Harvey Danger, and Jonathan Coulton.

The program spotlighted a variety of his musical interests, featuring interviews with artists such as Stephin Merritt, David Byrne, Matt Stone, and The Darkness.