Set in the context of high-impact prevention, this chapter provides a brief historical account of how theory application to HIV prevention has evolved from individual-level models to structural-level approaches. The chapter describes the value and limitations of applying behavioral science and social science theories to the pandemic and describes several models and theory-based approaches. It then proceeds to identify emerging, structural-level approaches to achieving population-level HIV prevention in developing and developed countries. The chapter distinguishes structural-level interventions from multilevel interventions, and it describes strengths and weaknesses of structural-level approaches to achieving high-impact prevention. In so doing, several critical principles of structural-level approaches are identified.