A shift in focus in the field of neuroHIV was clearly manifest at the 2014 Conference on Retroviruses and Opportunistic Infections (CROI), where a major emphasis was on the milder forms of neurologic morbidity, including cognitive impairment, seen in well-treated patients. Mechanisms of this persistent abnormality were investigated, including extensive analysis of the prevalence and associations of persistent HIV detection in cerebrospinal fluid (CSF) and characterization of persistent CNS immune activation. Another key emphasis was the early establishment of HIV replication and inflammation within the central nervous system (CNS) and the potentially salutary effect of very early HIV diagnosis and treatment in protecting the CNS from HIV-related injury. Mitochondrial function was identified as a potential mediator of a number of aspects of HIV-associated CNS dysfunction, including neurotoxicity associated with efavirenz, host genetic determinants of HIV-associated neurocognitive disorders (HAND), associations with direct measures of mitochondria in CSF, and metabolomic screening of CSF in HIV-infected subjects and those with HAND. Many studies employed laboratory rather than neuropsychologic end points, with a major focus on CSF biomarkers. Overall, neuroHIV presentations at CROI 2014 provided new insights into pathogenesis and treatment of the CNS, raising new challenges for researchers and practitioners aiming to optimize the status of the brain in people living with HIV infection.