The 2006 Conference on Retroviruses and Opportunistic Infections was marked by a record number of presentations focused on the neurologic complications of HIV infection. Key findings included the identification of the high prevalence of HIV-associated neurocognitive impairment (HNCI) in Western and East Asian populations; biomarkers that may be clinically useful in determining risk and treatment of HNCI, such as neurofilament protein, insulin resistance, leptin, soluble Fas, and total protein levels in cerebrospinal fluid; host genotypes that were associated with HNCI as well as antiretroviral toxic neuropathy; HIV envelope signature positions that were associated with HNCI and reduced CD4 dependence; the importance of combined antiretroviral drug penetration into the central nervous system for control of HIV replication; and an effective treatment for painful sensory neuropathy (capsaicin) and provocative preclinical data on treatments for HIV-associated neurocognitive impairment (rosiglitazone, glatiramer immunization). Together, these findings heighten concern for persistent neurologic diseases in antiretroviral therapy-treated individuals but provide guidance for their improved identification and treatment.