Central nervous system (CNS) immune privilege is an experimentally defined phenomenon. Tissues that are rapidly rejected by the immune system when grafted in sites, such as the skin, show prolonged survival when grafted into the CNS. Initially, CNS immune privilege was construed as CNS isolation from the immune system by the blood-brain barrier (BBB), the lack of draining lymphatics, and the apparent immunoincompetence of microglia, the resident CNS macrophage. CNS autoimmunity and neurodegeneration were presumed automatic consequences of immune cell encounter with CNS antigens. Recent data have dramatically altered this viewpoint by revealing that the CNS is neither isolated nor passive in its interactions with the immune system. Peripheral immune cells can cross the intact BBB, CNS neurons and glia actively regulate macrophage and lymphocyte responses, and microglia are immunocompetent but differ from other macrophage/dendritic cells in their ability to direct neuroprotective lymphocyte responses. This newer view of CNS immune privilege is opening the door for therapies designed to harness autoreactive lymphocyte responses and also implies (i) that CNS autoimmune diseases (i.e. multiple sclerosis) may result as much from neuronal and/or glial dysfunction as from immune system dysfunctions and (ii) that the severe neuronal and glial dysfunction associated with neurodegenerative disorders (i.e. Alzheimer's disease) likely alters CNS-specific regulation of lymphocyte responses affecting the utility of immune-based therapies (i.e. vaccines).