One of the characteristic features of microglia is their rapid activation in response to injury, inflammation, neurodegeneration, infection, and brain tumors. This review focuses on the role of the microglia in multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), and in the animal model of MS, experimental allergic encephalomyelitis (EAE). Microglial activation in MS and EAE is thought to contribute directly to CNS damage through several mechanisms, including production of proinflammatory cytokines, matrix metalloproteinases, and free radicals. In addition, activated microglia serve as the major antigen-presenting cell in the CNS, likely contributing to aberrant immune reactivity at this site. A mechanistic understanding of the way in which microglia are activated and ultimately inhibited is crucial for the formulation of therapeutic modalities to treat MS and other CNS autoimmune disease.