Over the past 15 years, novel pharmacologic treatments for the management of HIV/AIDS and severe mental illness have changed the prognosis and quality of life for millions of patients throughout the world. In HIV-infected patients, highly active antiretroviral therapy (HAART) has altered this epidemic in many countries and simpler, better-tolerated treatment regimens have resulted in many patients with HIV living longer and with an improved quality of life. In patients with severe mental illness, second generation antipsychotics (SGAs) or atypical antipsychotics have provided hope for many patients and families struggling with schizophrenia and bipolar disorder. Despite these advances in treatment, metabolic abnormalities, specifically the metabolic syndrome (MetS), are occurring at a greater incidence in both persons with HIV and persons with severe mental illness (SMI). Furthermore, patients with severe mental illness are becoming HIV-infected, and higher prevalence rates of severe mental illness are seen in HIV patients than the general population. This review examines the prevalence of metabolic abnormalities within each population and the impact of HAART and SGAs on the development of MetS. Overviewed are possible mechanisms for the development of MetS in these patients, standard monitoring protocols, and potential treatments for managing these metabolic issues. Finally, recommendations for monitoring and managing the intersecting, growing population of HIV/AIDS patients with severe mental illness are provided.