Microglia are the principal immune cells in the central nervous system (CNS) and have a critical role in host defense against invading microorganisms and neoplastic cells. However, as with immune cells in other organs, microglia may play a dual role, amplifying the effects of inflammation and mediating cellular degeneration as well as protecting the CNS. In entities like human immunodeficiency virus (HIV) infection of the nervous system, microglia are also critical to viral persistence. In this review we discuss the role of microglia in three diseases in which their activity is at least partially deleterious: HIV, multiple sclerosis, and Alzheimer's disease.