Ironically, David Krumholtz (who failed Algebra I twice, and hated math in school) plays a mathematician, while Dylan Bruno (who graduated from M.I.T. with a math-heavy engineering degree) plays the math-challenged F.B.I. Agent.
Diane Farr was pregnant for most of the first half of season three, and her character, Megan Reeves, was temporarily reassigned to Washington, D.C., to explain her absence during the second half (while Farr was on maternity leave). Because the showrunners didn't want to have to deal with the implications of Megan being pregnant and having a baby, they instead hid the pregnancy behind increasingly large folders, bags, desks, computer monitors, and finally, extras.
Navi Rawat's character is named "Amita Ramanujan", a reference to Srinivasa Ramanujan, a self-taught Indian mathematician, who worked in the first two decades of the twentieth century, most notably collaborating with G.H. Hardy in number theory.
"Cal Sci University" is modelled on the California Institute of Technology (Caltech) in Pasadena, developing characters loosely based on a Caltech professor and students. Portions of the series have been filmed on the Caltech campus. Gary Lorden, the chairman of the math department at Caltech, consulted for the show. The pilot episode was screened at Caltech as well, receiving a standing ovation at the end.
According to an interview that Rob Morrow gave to "The Jewish Journal of Greater Los Angeles", the Eppes family was not explicitly identified as Jewish until the fifth season, when Morrow asked the showrunners to make a point of it and to include a storyline in which his character, Don, starts to explore his religion (Morrow may have forgotten that in season four, episode five, "Robin Hood", Charlie does mention that he is Jewish). There were some implicit references to the family's Judaism earlier than that, however, including the comment in season one, episode one, "Pilot", about Alan serving brisket on Friday nights, and Don and Charlie's conversation in season three, episode three, "Provenance", about how it was weird that their mother had wanted a Christmas tree.
When the producers prepared to pitch the series concept to the network, they prepared an elaborate presentation about the story possibilities, anticipating that the executives would wary of agreeing to such a cerebral premise. However, the network executives were immediately enthusiastic part way through the pitch, that the series had good potential, and insisted on production beginning immediately.
The show's original concept had it take place at M.I.T., rather than CalTech. At that time, the character of Don was to be played by Gabriel Macht. While David Krumholtz was already cast as Charlie, other performers cast at that stage of the production included Michael Rooker and Anna Deavere Smith.
David Krumholtz and Peter MacNicol previously appeared in Addams Family Values (1993). MacNicol played a camp counselor who, in one scene, punishes Krumholtz for wanting to read a book about physics, instead of doing camp activities. This is a humorous contrast to this show, where the two play best friends, and MacNicol's character is a physicist.
David Krumholtz grew up in Rego Park, New York, and did his first commercial for a Forest Hills restaurant. Rob Morrow played Dr. Joel Fleischman from Forest Hills, on Northern Exposure (1990). Judd Hirsch played John Lacey, who lived in Rego Park, on Dear John (1988). Forest Hills and Rego Park are two adjoining areas in Queens, New York.
Rob Morrow, David Krumholtz, Judd Hirsch, Alimi Ballard, and Diane Farr were all born in or around New York City, New York. Although she was born in Fairfax, Virginia, Sabrina Lloyd's New York City connection, is that she moved there in 1988, at the age of eighteen.
Despite his character's genius on the show, David Krumholtz calls himself a "math idiot." He received math crib sheets to study along with the scripts that were prepared by Caltech professor Gary Lorden.