It is becoming increasingly clear that risk factors for use and trajectories toward desistance may differ significantly for men and women (e.g., Westermeyer &Boedicker, 2000). For example, recent work has uncovered different effects of monoamine genotypes (e.g., serotonin transporter, MAO-A) on male and female psychopathology and behavior (Sjoberg et al., 2007a;Verona, Joiner, Johnson &Bender, 2006). In addition, there is evidence that pubertal onset, childhood sexual abuse, and intimate partner violence (IPV) constitute unique risk factors for antisocial behavior and drug use among women compared to men (Dick, Rose, Kaprio, &Viken, 2000) and can predict drug relapse in women many years later in adulthood (Hyman, Garcia, &Sinha, 2006). Thus, a primary goal of the present application is to identify gender differences in biological and environmental risk factors for substance use outcomes as a way of advancing nuanced conceptualizations of female drug problems. The current project intends to (1) explore various gene by environment (GxE) effects on drug use outcomes, by examining different monoamine genes (5HTT, DRD4, MAO-A) and incorporating gendered environmental risk factors that are not commonly included in studies of drug use (e.g., intimate partner violence), (2) examine the extent to which GxE effects or individual risk factors are specific to substance use outcomes in women relative to men, and (3) identify multivariate models involving GxE effects and mediators of these effects to predict substance use pathways in men and women. The goal is to examine not only GxE effects (e.g., gene-by-abuse, gene-by-IPV) that directly influence substance use outcomes, but identify potential mediators (pubertal development, internalizing symptoms) in an effort to understand nuanced pathways for female substance use. The ultimate goal is to help in the development of tailored interventions to address gender-specific manifestations and etiologies. PUBLIC HEALTH RELEVANCE: Women's drug arrests have increased in the last two decades, whereas men's arrests have decreased. Thus, women's drug use has become a significant social problem. An innovative aspect of the project is the attempt to identify genetic and environmental factors that are female specific for substance use outcomes. Given important sex differences in biology, gene expression, and motives, this project can inform psychosocial and pharmacological treatments for substance use so that they are tailored to address gender-specific issues.