The major clinical and pathological features of the AIDS dementia complex (ADC), or synonymously, AIDS dementia, HIV-associated dementia, and minor cognitive motor disorder, were characterized almost 20 years ago. The fundamental difficulty is that although ADC is caused by HIV itself, the presence of HIV in cerebrospinal fluid (CSF) has little diagnostic specificity. The authors describe a pathogenetically based approach using a combination of CSF markers. In simple terms, ADC pathogenesis can be considered to result from the evolving interactions of three factors: the driving force, HIV; the modulating influence, immune dys-regulation; and the target, central nervous system (CNS). Importantly, alteration of the immune system is likely important in permitting progressive HIV infection of the CNS and in determining its pathogenic character. In the immunological marker category, the most promising measurements are those of CSF neopterin and monocyte chemotactic protein 1 (MCP-1). The uncertainty of ADC diagnosis more than 20 years after its initial characterization remains a conspicuous shortcoming both in the clinic and in clinical trials. There is still a pressing need to develop objective, laboratory-based markers to aid in predicting development of ADC, establishing ADC diagnosis, and appraising disease activity, including treatment responses. While it is likely that the foundation has been laid with a number of exploratory studies already published, these have fallen short of practical clinical application.