The human immunodeficiency virus-1 (HIV-1) commonly affects cognitive, behavioral and motor functions during the disease course. The neuropathogenesis of viral infection revolves around neurotoxins produced from infected and immune-activated mononuclear phagocytes (MP; perivascular macrophages and microglia). Direct infection of neurons occurs rarely, if at all. Neurologic disease arises in part as a consequence of MP metabolic dysfunction. Although the advent of highly active antiretroviral therapy (HAART) has attenuated the incidence and severity of neurologic disease, it, nonetheless, remains a common and disabling problem for those living with HIV-1 infection. Adjunctive therapies are currently designed to ameliorate clinical outcomes and are included in the therapeutic armamentarium. Anti-inflammatory drugs that inhibit cytokines, chemokines and interferons linked to neurodegenerative processes can significantly ameliorate neuronal function. HIV-1 neurotoxins have the unique ability to up-regulate glycogen synthase kinase-3beta (GSK-3beta) activity that in turn elicits neuronal apoptosis. GSK-3beta inhibitors are neuroprotective in animal models of Neuro AIDS. They are also currently in Phase 1 clinical trials designed for safety and tolerability in patients with HIV-1 infection. Neurotrophins are only beginning to be realized for their therapeutic potential in HIV-1 associated neurologic disease. This review article provides a broad overview of neuroprotective strategies for HIV-1 infection and details how such strategies act and may be implemented for treatment of human disease.