Teachers' formal accountability and duties have been the focus of high-stakes educational reforms, for instance in the context of national accountability systems. Yet, teachers' sense of personal (rather than formal) responsibility and willingness to assume responsibility for their teaching and students remains an understudied area. The main purpose of this study was to investigate contextual and person-specific predictors of teachers' sense of personal responsibility, as well as the potential implications of teachers' personal responsibility for their instructional approaches and wellbeing. A path analysis indicated that high school teachers (n = 287) who felt responsible for their teaching and students reported higher levels of work engagement and job satisfaction than less responsible teachers, and were more likely to endorse mastery-oriented instructional practices that emphasized student effort, task mastery, and individual growth. Teachers' perceptions of their school's social climate (teachers' evaluations of their relationships with students), their sense of teaching self-efficacy, and incremental beliefs of intelligence emerged as positive predictors of teacher responsibility. Teacher responsibility partially mediated the positive effects of these predictors on teachers' wellbeing and mastery-oriented instructional practices. The results suggest that both contextual (e.g., school climate) and person-specific (e.g., self-efficacy) factors can contribute to teachers' sense of personal responsibility, and that responsibility, in turn, can have positive implications for teachers' wellbeing and instructional practices. Directions for future research and practical implications are considered.