Mental health problems including substance abuse are one of the most significant areas of co-morbidity for people living with HIV/AIDS (PLWHA) worldwide and are more prevalent among PLWHA than the general population. An estimated 50% of PLWH meet criteria for one or more mental or substance use disorders, which are associated with suboptimal HIV treatment outcomes including late ART initiation and delayed viral suppression. Mortality rates for PLWHA having a Major Depressive Disorder (MDD) is twice as high as for those without a MDD. Positive mental health is associated with improved physical health outcomes across a range of chronic illnesses, but – in addition to negative psychological responses to an HIV diagnosis, disease progression, associated stigma, and loss of social support – the chronic inflammatory response to HIV infection is hypothesized to contribute to elevated rates of mental health problems among PLWHA. Further, HIV effects on the brain contribute to neuro-cognitive disorders as well as disturbed affect regulation among PLWHA. Unfortunately, the stigma embodied in discriminatory social structures, policy, and legislation, results in a disparity between physical and mental health care services, with lower availability, accessibility, and quality of services for the latter. Integration of services to screen and manage mental health and substance use disorders into HIV care settings is a promising strategy to improve mental health and HIV treatment outcomes among PLWHA, including in resource-constrained settings. A range of psychological interventions have been shown to improve mental health among PLWHA, including reducing depression and anxiety and increasing quality of life and psychological well-being. Further, treatment for mental disorders and behavioral (i.e., adherence) interventions has an additive effect, positively affecting HIV health outcomes. While significant challenges remain for meeting the high demand, especially in resource-constrained settings where HIV is most prevalent, addressing mental health co-morbidities (i.e., screening and treatment) in the context of HIV prevention and care is essential for achieving optimal outcomes along the HIV prevention and treatment continua. We may have the biological tools to ‘end AIDS,’ however we will not be able to achieve ‘ending the epidemic’ (EtE) goals, if we do not address mental health co-morbidities among our most vulnerable populations.