Achieving and sustaining high levels of adherence to medication regimens is essential to improving health outcomes, but continues to be a challenge for a sizable proportion of patients. Decades of research suggests that medication adherence is determined by a complex constellation of factors. Social-behavioral science research has focused on creating frameworks that identify which contextual, personal, social, or drug-related factors appear to most influence adherence. Comprehensive models of adherence propose specific structural relationships between these factors that can be used to plan for, implement, and monitor programs that seek to optimize adherence. The use of social-behavioral models offers multiple advantages in both practice and research environments; however, the breadth and depth of these models can deter many from engaging in this important exercise. To promote the use of social-behavioral frameworks and models of adherence, we provide a brief overview of the advantages in using a social-behavioral lens in adherence work, a sampling of models used in HIV medication adherence research that have high generalizability to other conditions, and practical guidance for grounding adherence promotion strategies in evidence informed by social-behavioral science research.