There has been a general recognition of a syndemic that includes HIV/AIDS and serve mental illnesses including schizophrenia, major depression, bipolar disorder, post-traumatic stress disorder, and others. The pathophysiology and direction of effects between severe mental illness and HIV infection is less clear however, and relatively little work has been done on prevention and treatment for people with these complex, co-occurring conditions. Here we present the most recent work that has been published on HIV and mental illness. Further, we describe the need for better treatments for "triply diagnosed persons"; those with HIV, mental illness, and substance abuse and dependence. Finally, we describe the potential drug-drug interactions between psychotropic medications and anti-retrovirals, and the need for better treatment guidelines in this area. We describe one example of an individually tailored intervention for persons with serious mental illness and HIV (PATH+) that shows that integrated community-based treatments using advanced practice nurses (APNs) as health navigators can be successful in improving health-related quality of life and reducing the burden of disease in these persons.