While it is clear that HIV-1 can cause CNS dysfunction, current approaches to classification and diagnosis of this dysfunction rely on syndromic definitions or measures of abnormality on neuropsychological testing in the background context of HIV-1 infection. These definitions have been variably applied, offer only limited sensitivity or specificity, and do not easily distinguish active from static brain injury. Supplanting or augmenting these approaches with objective biologic measurements related to underlying disease processes would provide a major advance in classification, diagnosis, epidemiology, and treatment assessment. Two major avenues are now actively pursued to this end: 1) analysis of soluble molecular markers in CSF and, to a lesser degree, in blood, and 2) neuroimaging markers using anatomic, metabolic, and functional measurements. This review considers the rationale and prospects of these approaches.