Innate immune responses in the central nervous system (CNS) have key roles influencing both physiological and pathological processes. Microglia are innate immune effector cells that reside within the CNS. These inflammatory cells are constantly surveying their external environment and rapidly respond to a variety of molecules that signal changes in CNS homeostasis. In response to these signals, microglia influence neuronal connections, modulate the functions of other glia, and mediate inflammatory responses to disease or injury. In parallel with the regulation of inflammatory responses outside of the CNS, investigators have observed that microglia are capable of heterogeneous responses to exogenous and endogenous signals. While much of this molecular and morphological heterogeneity is regulated by gene transcription, there is ample evidence that microglial behavior is determined, in part, by epigenetic regulation. Recent work has demonstrated that processes involving DNA methylation, histone modification, and noncoding RNAs also have important roles in modulating neuroinflammation. Here I will review the evidence supporting a role for epigenetic regulation of neuroinflammation and describe how this might influence the outcome of several CNS disorders, including addiction, infection, multiple sclerosis, and stroke.