Despite the enormous success of antiretroviral treatment (ART) it is becoming clear that people living with HIV are experiencing high rates of both cognitive impairment, and major depressive disorder (MDD). Added to this the HIV infected population is aging and there are concerns that living with chronic HIV infection may exacerbate the risk of other neurodegenerative disorders. In this talk I will summarize the neuropathology that occurs due to HIV infection of the brain and how this relates to the clinical presentation of HIV-associated neurocognitive disorder (HAND). I will outline the approach to the recognition and diagnosis of HAND as well as implications for treatment. This will be followed by a discussion of the emerging field of the neuropathology and clinical presentation of MDD in the setting of HIV and our current knowledge about the potential interaction of HIV, aging and neurodegenerative diseases.