Systematic treatment selection (STS) is an evidence-based, principle-driven, and culturally grounded psychotherapy that guides clinicians in their day-to-day work of helping clients change. Its key procedures start with an ongoing assessment of patients’ functional impairments, resistance levels, coping styles, and other empirically established moderators of change. The clinician then selects treatments that “fit” the individual client and develops a treatment plan based on the moderators identified in the first step. This chapter reviews STS’s fundamental tenets, assessment and formulation, applicability and structure, and the role of the therapy relationship. A detailed case example illustrates the key processes. The chapter also provides diversity considerations, discusses outcome research, and concludes with future directions of STS.