The long-term development of female substance use, substance-related problems, and substance use disorders (SUDs) is poorly understood. In at least two ways, females appear more vulnerable to substance abuse and dependence compared to males: they demonstrate more rapid development from onset of use to SUD, and a higher propensity to develop comorbid psychopathology. In addition, early onset of substance use carries a higher risk of developing an SUD among females compared with males. The main goal of the proposed research is to investigate the early phases in the development towards frequent substance use, substance-related problems, and SUD. This proposal describes a substudy to the NIMH-funded Pittsburgh Girls Study (N = 2,451; 52% African-American, 41% Caucasian), an investigation of the development of antisocial behavior and delinquency in four age cohorts of girls, initially assessed at ages 5 to 8. The main study is now in its fifth yearly assessment (ages 9 to 12), and will continue for another 4 years. The proposed study requests a continuation of earlier funding by NIDA, which supported examination of the precursors and explanatory factors associated with girls' early substance use. The proposed research, through five yearly follow-up assessments of the child, the main caretaker, and teachers, extends this line of inquiry into the developmental period from age 10 to 17, when we expect that girls' substance use, substance- related problems, and comorbid conditions will increase. The aims of the proposed research are to: (1) describe developmental sequences of substance use by girls during the transition from childhood into adolescence within and across substances; (2) examine developmental sequences of substance use by girls in conjunction with the developmental course of comorbid conditions, especially psychopathology and other behavior problems; and (3) determine proximal and distal risk and protective factors (both generic and female-specific) for different developmental sequences of substance use by girls. These three aims, in conjunction with the data on early substance use and attitudes already collected, will link childhood factors to substance use during adolescence. The Pittsburgh Girl Study is one of the very few studies in the USA that can examine these relationships from childhood through adolescence.