Most women in homeless populations are mothers, the majority being single mothers. Retaining child custody is challenging in homeless circumstances. Prospective longitudinal studies are needed to follow the moving pieces of housing and child custody in the context carefully-assessed psychiatric and substance use disorders over time. A 2-year prospective longitudinal study of an epidemiologic sample of individuals with literal homelessness included 59 mothers. Annual assessments included structured diagnostic interviews, detailed assessment of homeless circumstances, urine drug testing, and service use documented by both self report and data from agencies serving these individuals. More than one-third of the mothers consistently lacked child custody throughout the course of the study and the proportions of mothers with child custody did not increase significantly. Nearly one-half of the mothers had a current year drug use disorder at baseline, including cocaine disorder in most. Continuing lack of child custody over time was associated with longitudinal lack of housing and use of drugs. The importance of drug use disorders in the longitudinal course of child custody points to a critical need for formal substance abuse treatment, not just initiatives to decrease drug use, in helping mothers regain and maintain custody of their children.