Members of the major histocompatibility complex (MHC) class I family of proteins are well known for their central role in the adaptive immune system, where they present self and non-self peptides for immune surveillance. Although the brain has been long considered immune privileged, in part because of an apparent lack of neuronal MHC class I, it has since been shown that MHC class I proteins are expressed by normal, uninfected neurons. Moreover, expression of MHC class I is unusually dynamic in the developing and adult brain, and MHC class I levels in neurons can be regulated by endogenous and exogenous electrical activity. Unexpectedly, several recent studies find that MHC class I is required for distinct activity-dependent events during brain development, adult plasticity, and in response to injury. Together, these studies indicate a novel role for MHC class I proteins in translating electrical activity into changes in synaptic strength and neuronal connectivity in vivo.