The band began hinting that the next children's album would be science-themed via interviews around the release of 123s, but the actual title of the album was not confirmed until an August 2008 interview with John Flansburgh for Blogcritics Magazine.

The album had been in production since at least late 2007, as a very short sample clip of the music video for the song "How Many Planets" was posted in January 2008 to Colourmovie's website.

The band also hired a scientific consultant for this project because, as Flansburgh admitted, "frankly, I was a terrible science student in high school.

Here Comes Science features the songs "I Am a Paleontologist" and "Speed and Velocity", on which bass guitarist Danny Weinkauf and drummer Marty Beller sing their own compositions (respectively).

"I Am a Paleontologist" features spoken appearances from Weinkauf's two children, Lena and Kai.