This chapter aims to characterize and explain pathological substance use from a developmental perspective. We first review key definitions (e.g., substance use disorder) and epidemiologic findings (e.g., age patterns). We then discuss etiology of problematic substance use with an organizational framework that distinguishes three key risk pathways emphasizing (1) deviance proneness, (2) stress and negative affect, and (3) pharmacological effects, respectively. We highlight components of these pathways that represent promising modifiable targets for prevention and treatment interventions. In addition to etiology, we also consider the normative trend toward “maturing out” of problematic substance use beginning in young adulthood. While most past literature on maturing out has emphasized young adult adoption of new roles and responsibilities, we also consider recent evidence for effects of young adult personality maturation. As possible mechanisms of naturally occurring desistance, these role- and personality-related processes could inform interventions aimed at goading similar changes in substance involvement. We also note that the normative trend toward maturing out in fact extends well beyond young adulthood, and we discuss factors that may be particularly salient to midlife and older adult desistance within a lifespan developmental framework (e.g., problem recognition, substance-related health concerns).