HIV-D in the era of HAART has a decreased incidence but a stable prevalence. CNS infection itself appears to be attenuated with a greater frequency of patients with milder forms of cognitive impairment, less correlation with CSF HIV RNA levels, and decreased markers of CNS inflammation. Surrogate markers of HIV-D from the pre-HAART era need to be re-evaluated in patients on HAART. As patients with HIV infection enter their 5th and 6th decades of life, new surrogate markers such as vascular and neurodegenerative disease markers need to be evaluated further to help differentiate between HIV-associated cognitive impairment and impairment due to co-morbid disease such as cerebrovascular disease or Alzheimer's disease. Therapies including both antiretroviral drugs and adjunctive therapies need to be examined further to improve treatment in patients with progressive HIV-associated cognitive impairment.