Human immunodeficiency virus-1 (HIV) infection of the central nervous system may cause a neurological syndrome termed HIV-associated neurocognitive disorder (HAND) which includes minor neurocognitive disorders or a more severe form of motor and cognitive impairments. Although treatment with highly active antiretroviral agents decreases the load of HIV in the brain, the prevalence of mild forms of HAND is actually increased due to longer life. Therefore, adjunctive and combined therapies must be developed to prevent and perhaps reverse the neurologic deficits observed in individuals with HAND. Key to developing effective therapies is a better understanding of the molecular and cellular mechanisms by which the virus causes this disorder. A number of HIV proteins has been shown to be released from HIV-infected cells. Moreover, these proteins have been shown to possess neurotoxic properties. This review describes new evidence of a direct interaction of the HIV protein gp120 with neurons, which might play a role in the etiopathology of HAND.