Substance use is highly prevalent among people living with HIV/AIDS, is often comorbid with other mental health problems, related to poor HIV medical outcomes, and, is associated with poor medication and treatment adherence. The current review reports on the recent state of the literature in terms of substance use and its relation to HIV medication and treatment adherence, and offers recommendations for advancing treatment and secondary HIV prevention efforts. Identifying substance users within HIV primary care and developing, evaluating, and refining integrative substance use-mental health-adherence interventions may be clinically important targets for effective disease management and may contribute to secondary HIV prevention efforts.