CD8+ resident memory T cells (TRM cells) act as a first line of defense in tissues and are able to respond rapidly to pathogens and recruit other immune cells. In the Journal of Experimental Medicine, Merkler and colleagues demonstrate the existence of a de facto population of brain-resident TRM cells (bTRM cells) in mice. Intracranial viral infection generates bTRM cells that are located chiefly along barrier surfaces such as the choroid plexus or meninges and less so in the parenchmya itself. These bTRM cells proliferate homeostatically and do not require input from the periphery for their long-term maintenance, nor are peripheral memory T cells needed for the bTRM cells to protect the brain from reinfection. Viral reinfection prompts a rapid response from bTRM cells marked by evidence of degranulation and interferon-γ production. Both perforin and interferon-γ are required for bTRM cell–mediated protection. The brain can therefore harbor TRM cells that act as an effective local barrier to viral reinfection.