Although it is often described as "immunologically privileged," the brain can display vigorous immune activity, both clinically and experimentally. The underlying control mechanisms are under active study. Here we shift attention from the brain as a whole to its diverse microenvironments. We review evidence that immune regulation in the brain is site-specific, and that local neurochemicals contribute to the site-specific control. Key points are illustrated by recent work from a rat model in which local injection of the proinflammatory cytokine, IFN-gamma, was used to modulate 2 essential aspects of the cell-mediated immune response: T cell entry from the blood, and expression of the MHC proteins that are needed to present antigen to the newly entered T cells. A growing number of neurologic disorders are known to be exacerbated by the immune/inflammatory network. Understanding the factors that influence local immune function may help explain the distribution of localized CNS damage and, more importantly, may suggest new therapeutic approaches for both desirable and unwanted responses.