The innate immune system is multifaceted, comprised of preformed factors, cells, and many proteins and lipid mediators produced by those cells. In the CNS these are critical in initiation and amplification of the inflammatory response and in the subsequent elicitation of the specific T cell response to viral encephalitis. Cells that are resident in brain parenchyma and peripheral cells that are recruited both play key roles in the hosts's responses. Unlike the peripheral compartments, in the CNS, non-cytolytic means of eliminating viral infections have been critical, since, in contrast to columnar epithelial cells, neurons are non-renewing. When the innate immune responses are inefficient or absent in viral encephalitis, pathology is more likely. Much more work remains to elucidate all of the critical cells and their mediators, as well as to develop new therapies for infections of the CNS.