Prior research points to a variety of factors that influence student persistence in science, technology, engineering, and mathematics (STEM) degree programs. Little attention, however, has been given to how STEM faculty understand these processes and subsequently frame their role in supporting students. To address this gap, this article reports on an analysis of the interpretive frames through which instructors of introductory STEM courses make sense of the factors that influence student persistence and success in STEM degree programs. Interview data were collected from 73 instructors of introductory STEM courses at six predominantly white institutions of higher education across the United States. The coding of interviews included concept and theoretical coding using cluster analysis, multidimensional scaling, and correspondence analysis. The coding process identified six unique interpretive frames through which instructors made sense of student persistence. These frames varied greatly in the ways that students were perceived to have agency in shaping their persistence and success in STEM, as well as the steps that can be taken to ameliorate social inequalities in these outcomes. The findings thus have important implications for how researchers and program designers frame strategies that can support student persistence outcomes in STEM degree programs.