Toll-like receptors (TLRs) are a family of pattern-recognition receptors expressed on cells of the innate immune system that allow for the recognition of conserved structural motifs on a wide array of pathogens, referred to as pathogen-associated molecular patterns, as well as some endogenous molecules. The recent emergence of studies examining TLRs in the central nervous system (CNS) indicates that these receptors not only play a role in innate immunity in response to infectious diseases but may also participate in CNS autoimmunity, neurodegeneration, and tissue injury. This review summarizes the experimental evidence demonstrating a role for TLRs in the context of CNS inflammation in both infectious and noninfectious conditions.