The main purpose of this study was to investigate the association between child abuse and substance use among homeless women based on a framework of General Strain Theory, which emphasizes the strong relationship between deviant behaviors and personally experienced strain. In this study, as the strain associated with substance use, child abuse experience in the past was assessed. This research tested three hypotheses about (a) the association between physical and sexual abuse during childhood and substance use (heavy drinking, marijuana use, and crack cocaine use), (b) the mediating effect of depressive symptoms, and (c) the moderating effect of positive social supports on the relationship between abuse during childhood and substance use with a survey and interview data of a randomly selected sample of 445 homeless women in a temporary shelter setting in Los Angeles County between June 2007 and March 2008. Although the results indicated that abuse during childhood was not significantly associated with any form of substance use, the results of multivariate analyses indicated that depressive symptoms fully mediated the four relationships (p < .01; physical abuse and heavy drinking, physical abuse and crack cocaine use, sexual abuse and heavy drinking, and sexual abuse and crack cocaine use). The results of this study also indicated that positive social supports significantly moderate the effect of physical (p < .01) and sexual (p < .05) abuse experience on heavy drinking, which implies that positive social supports would be significant to reduce substance use among homeless women who had a history of physical and sexual abuse during childhood.