Non-human primate models of AIDS and neuroAIDS have been useful to study AIDS in humans in general and neuroAIDS in particular. Important information concerning target cells of infection, mechanisms of immune activation and pathology and cell traffic has been made in non-human primate models. To date observations in SIV infected monkey models have predicted or paralleled monocyte/macrophage biology with HIV infection and neuroAIDS. In this brief review we discuss a CD8+ T lymphocyte depletion model of rapid AIDS which results in a high incidence of SIV encephalitis. Specifically we review recent observations we have made using this model concerning monocyte turnover, monocyte/macrophage activation, macrophage derived biomarkers of disease and novel therapeutic approaches to AIDS and CNS pathology. Importantly, all observations made in the rapid model of AIDS discussed here are important and relevant to HIV infection of humans, even in the current era of anti-retroviral therapy that maintains HIV in plasma below the limit of detection.