The California Medical Assistance Team (CAL-MAT) program is coordinated by the California Emergency Medical Services Authority (EMSA). The program was developed to deploy and support medical personnel for disaster medical response. During the coronavirus disease (COVID-19) pandemic, the program and missions grew rapidly in response to medical surge, programs for testing and vaccination, and other concurrent disasters. CAL-MAT enrollment increased 10-fold from approximately 200 members at the beginning of 2020, to an estimated 2200 members by June 2021. This article describes the flexible use of a state-managed disaster medical response program within California and some of the challenges associated with rapid expansion and varied demands during the COVID-19 surges of March 2020–March 2022. CAL-MAT may serve as a model for development of similar state-sponsored or other disaster medical response teams.