Highly Active Antiretroviral Treatment, despite its striking systemic efficacy, might be incompletely effective in some organs and tissues thus favouring residual HIV replication and damage. The central nervous system (CNS) is a key organ in this setting and several data have reported a worrisome prevalence of neurocognitive deficits in effectively treated HIV-positive patients. In this talk data on the potential mechanisms underlying CNS disease in HIV-positive patients including early treatment, residual HIV replication, potential drug-associated neuronal toxicity and vascular abnormalities will be presented. Following a brief description of the pharmacokinetic determinants of antiretroviral penetration and activity in the CNS (including cellular targets), the available evidence on the effect of different antiretrovirals on CNS HIV will be reviewed as well as the studies involving ARV combinations for treating patients with CNS disorders including the ongoing discussion on the use of the CNS concentration/effectiveness (CPE) score and the effect of unconventional antiretroviral regimens (based on more or less than three drugs). Finally, studies on adjunctive therapies will be presented and potential therapeutic targets reviewed.