Alcohol and drug use are significant public health problems facing homeless women, but few prospective studies have examined risk and protective factors for substance use in this population. This 6-month prospective study identified psychosocial, behavioral, and economic predictors of drinking to intoxication, crack use, and marijuana use in a probability sample of 402 women living in temporary shelter settings in Los Angeles County with a simple majority of homeless residents (92% of these women had a history of homelessness). Engaging in sexual risk behavior and having depressive symptoms were risk factors for more frequent intoxication, marijuana use, and crack use. Drinking to intoxication was additionally predicted by perceived HIV susceptibility, lower social support, more avoidant and less active coping, and lower self-esteem. Additional predictors of marijuana use included partner alcohol misuse and less social support, whereas more frequent crack use was additionally predicted by partner alcohol misuse, lack of economic resources, and more avoidant and less active coping. These findings suggest that effective substance use programs may need an integrative approach that addresses other types of risk behaviors, assists women in strengthening their support networks and learning effective coping skills, and provides access to basic services (e.g., housing, health care). For women in relationships, there may be a further need to address issues of partner substance use.