Substance use disorders and psychiatric illness commonly co-occur in what is known as dual diagnosis. With the spread of HIV infection in persons with dual diagnoses, the triple diagnosis has emerged as a clinically challenging condition for primary care physicians, addiction medicine specialists, and psychiatrists. Existing data support the high prevalence of triple-diagnosis patients in psychiatric, substance abuse, and HIV treatment settings. This review highlights the features of substance abuse-psychiatric illness and its association with changes in antiretroviral therapy use, adherence, and HIV treatment outcomes. An integrated and interdisciplinary approach addressing substance abuse and mental health issues should be a primary element of comprehensive HIV care. Evaluating the safety and efficacy of psychopharmacologic and psychotherapeutic interventions and understanding the complex interactions among the components of the triple diagnosis are areas for future research. Service delivery and intervention models based on "1-stop shopping" should be developed and put into practice in order to optimize clinical outcomes.