The research proposed in this application aims to understand genetic and environmental factors that promote desistance or continuation of problematic substance use and associated high-risk behaviors that began in adolescence. We propose an ~12-year follow-up (6 years after an initial 6-year follow-up) of an extremely affected adolescent sample as they transition into adulthood; this is a critical developmental period when we expect a portion of these individuals to decrease or desist problematic substance use and associated high-risk behaviors, while others will persist with the most serious, destructive behaviors leading to devastatingly high rates of morbidity and mortality. Our central goal is to understand the genetic and environmental factors that delineate these life trajectories. Results from our longitudinal research demonstrate that adolescent-onset substance users, who primarily exhibited abuse of and dependence on marijuana, nicotine, and alcohol during adolescence, progressed in the severity of their substance use five years later. As young adults, they report dramatically high rates of lifetime cocaine (29.2%), amphetamine (29.2%), and opiate (10.8%) use disorders as well as HIV/AIDS-related risk behaviors such as injection drug use (11%) and risky sexual behaviors. Indeed, when compared with community samples, these individuals report more than twice the number of lifetime sexual partners and a 33% higher rate of unprotected sex. Furthermore, they exhibit alarming rates of adult incarceration (55%) and early death (2.6%). This proposal extends our multiple-PI collaboration focused on the genetic epidemiology of adolescent-onset drug dependence. The three specific aims are to: 1) Identify distinct developmental trajectories of substance use, antisocial, and HIV risk behaviors in probands and siblings from adolescence to adulthood. a) Test initial characteristics of the adolescents, such as sex, severity of early onset substance use disorders (SUDs) and conduct disorder (CD), and neurocognitive functioning (e.g., disinhibition) that predict these trajectories and b) Test whether adult resources such as treatment for SUDs, housing stability, occupational stability, and social support are associated with these trajectories. 2) Determine the genetic and environmental architecture of developmental trajectories of substance use disorders, antisocial and HIV risk behaviors. a) Test the moderating role of social context, such as SES, criminal justice involvement, substance abuse treatment/self-help involvement, and stressful life events, in altering genetic influence and b) Test whether moderating effects vary across developmental periods (adolescence, young adulthood, and adulthood). 3) Test the influence of shared versus specific etiologic influences on measures of SUDs, antisocial behaviors, and HIV risk behaviors across development.