The importance of HIV cognitive impairment, including HIV associated dementia (HAD) and minor cognitive/motor disorder, has continued in the era of highly active antiretroviral therapy (HAART). Despite the relative efficacy of HAART in controlling HIV disease, there is no treatment which specifically targets the cause of HAD nor promotes neuronal protection from the effects of the virus. Much work has been done to elucidate the complex signalling pathways, effects of virus and viral proteins, and dysregulation of endogenous targets which lead to HIV associated neurotoxicity, but the concise mechanism remains elusive. It is widely accepted that the majority of viral replication in the brain occurs in monocyte derived macrophages (MDM) and microglia, and immune activation of these cells, along with astrocytic cells, may be the most important cause of neurotoxicity in the central nervous system (CNS). Additional complications arise when co-factors such as drug use, age related neuropathology, and other viruses are present. Further exploration of the molecular mechanisms leading to HIV neurotoxicity and neurodegeneration may reveal targets for prophylactic neuroprotective or other CNS-specific drugs. Given the variable success of the current HAART drugs against virus in the CNS, such therapies would greatly benefit the HIV infected population as they live longer and more productive lives.