Early in the HIV/AIDS epidemic, the deleterious consequences of HIV-1 infection in the central and peripheral nervous system were described. They were considered to be due to severe immunosuppression, and encephalitis was considered predominantly attributable to concomitant cytomegalovirus (CMV) infection. Antiretroviral agents (ARVs) was further noted that patients with HIV-1-associated neurocognitive disorders would initially improve but later progress despite the continued use of zidovudine (ZDV). In December 1995, the highly active antiretroviral therapy (HAART) era began when the protease inhibitors (PIs) were introduced into practice with the FDA approval of saquinavir. A number of changes have occurred across the spectrum of HIV-1-associated neurocognitive disorders since the introduction of HAART. The incidence of HIV-1-associated dementia (HAD) is widely reported to have decreased following the introduction of HAART; however, the incidence of HIV-1 encephalopathy (as defined neuropathologically) appears to have increased, although interestingly, both the neuropathological and the clinical aspects of the syndrome seem to be less severe than those observed in the pre-HAART era. In addition to the above-mentioned changes in clinical manifestations of HIV-1-associated neurocognitive disorders, their underlying pathophysiology has also evolved. Aside from the original focus on virologic (pathogen), inflammatory/immunologic (host response), and comorbid infection factors, there are now three additional categories of pathogenic factors that demand attention. These are the vascular, medication toxicity, and genetic factors. Molecular investigations of multidrug resistance (MDR) resulted in the isolation and characterization of genes coding for several associated proteins, including P-glycoprotein and the MDR-associated protein MRP1.