Psychological factors have been implicated in STEM persistence but remain poorly understood. In particular, the role of self-regulation--the cognitive, behavioral, and emotional skills that allow individuals to work efficiently toward their desired goals, especially when under stress--has received minimal attention. Psychological factors may be particularly important for persistence by underrepresented minority (URM) students, many of whom face significant barriers to success in STEM. We examined the extent to which self-regulation predicts STEM persistence in 755 STEM students and whether minority status moderated self-regulation's associations with STEM persistence. We found minimal differences in self-regulation styles between URM and nonunderrepresented minority students. Baseline cognitive-emotional self-regulation predicted intentions to persist in a science career, using alcohol and drugs to cope with stress predicted less persistence in STEM major across the year, and only URM status predicted end-of-year GPA. Cognitive-emotional self-regulation was more strongly related to intentions to persist for URMs, and use of humor coping was related to lower GPA especially for URMs. Future research is needed on self-regulation skills and students' trajectories of STEM success.