Before the ground-breaking discovery of antiretroviral therapy (ART), an HIV diagnosis was considered a death sentence with many HIV-infected people dying from AIDs-related illnesses. Nonetheless, decades later, the life expectancy of people living with HIV is approaching that of the general population. Despite the ongoing global efforts in tackling the HIV epidemic thus far, a variety of new challenges with an adverse effect on the quality of life of people living with HIV still exist. Of particular concern is the array of neuropsychiatric comorbidities associated with long-term HIV including mental health problems, neurocognitive disorders, drug and substance abuse and functional impairments. The persistent occurrence of these complications in the ART period has been associated with direct effects of HIV to the brain, emergence of virologic failure, direct and indirect effects of some ART drugs, psychosocial challenges, and concurrent illnesses.