The rich research literature on psychotherapies for children, adolescents, and adults has identified several interventions that can ameliorate or effect significant change in psychiatric disorders and a variety of social, behavioral, and emotional problems and can enhance medical outcomes and recovery. After decades of psychotherapy research and thousands of studies, there is no evidence-based explanation of how or why even the most well-studied interventions produce change, that is, the mechanisms through which treatments operate. This article discusses central requirements for demonstrating mediators and mechanisms of change. Also presented are promising lines of work to identify mediators and mechanisms, ways of bringing to bear multiple types of evidence, recommendations to make progress in understanding how therapy works, and conceptual and research challenges in evaluating mediators and mechanisms.