Objective: The diagnosis and treatment of cancer are highly stressful experiences that can profoundly affect emotional and physical well-being. Hundreds of longitudinal investigations that identify risk and protective factors for psychological and physical adjustment in adults living with cancer and numerous randomized controlled psychosocial intervention trials constitute the relevant knowledge base on factors that promote quality of life and health in this group. A critical step for the development of maximally effective interventions is to attend to the mechanisms by which interventions achieve their effects. Our goals in this article are to provide a rationale for theoretical and empirical consideration of mediating processes in intervention research, review existing randomized psychosocial intervention trials for adults diagnosed with cancer that include evaluation of mediators, and offer recommendations for research. Method: We draw from the existing conceptual and empirical literature regarding examination of mediating processes and review 16 randomized controlled trials that include evaluations of mediators. Results: The current conceptual and empirical literature on evaluating mediators of interventions provides robust rationales and procedures for testing mediators of psychosocial interventions for adults diagnosed with cancer. Promising classes of mediators include alterations in cognitions (i.e., expectancies, illness representations), self-efficacy for using coping strategies and other skills targeted by the intervention, psychological and physical symptoms related to cancer (e.g., mood disturbance, pain), and psychosocial resources (e.g., self-esteem). Conclusions: Focused attention to mechanisms underlying the efficacy of interventions can help integrate theory, research, and practice to promote the well-being and health of individuals with cancer. (Contains 1 table.)