In 1972, Mayne helped found the Southern California Institute of Architecture (SCI-Arc), where he is a trustee and the coordinator of the Design of Cities postgraduate program.

In 1972, Mayne abruptly left Cal Poly Pomona[7] and collaborated with five other students and educators whom he met at while at USC, to create the Southern California Institute of Architecture, or SCI-Arc.

[6] SCI-Arc was "to bring to Los Angeles the critical attitude toward the profession that was being practiced at Cooper Union in New York and the Architectural Association in London.

The firm's design philosophy arises from an interest in producing work with a meaning that can be understood by absorbing the culture for which it was made, and their goal was to develop an architecture that would eschew the normal bounds of traditional forms.

Beginning as an informal collaboration of designers that survived on non-architectural projects, its first official commission was a school in Pasadena, attended by Mayne's son.

Under the Design Excellence program of the United States government's General Service Administration, Thom Mayne has become a primary architect for federal projects.

Recent commissions include: graduate housing at the University of Toronto; the San Francisco Federal Building; the University of Cincinnati Student Recreation Center; the Science Center School in Los Angeles, Diamond Ranch High School in Pomona, California; and the Wayne L. Morse United States Courthouse in Eugene, Oregon.

In recent years, such visual effect has been made possible increasingly through computer design techniques, which simplify the construction of complex forms.

[10] In late summer 2002, Mayne was asked by New York magazine to contribute a proposal for the World Trade Center site, where recovery and cleanup had just ended.

[22] In June 2014, Mayne bought the Cheviot Hills, Los Angeles house that noted writer Ray Bradbury had lived in for 50 years.

When queried, the Morphosis office reported that the house was not being razed, but "deconstructed" so that some of the materials could be recycled – including into 451 sets of bookends – a longer and more complicated process.