Multiple Sclerosis (MS) is an autoimmune disease in which Central Nervous System (CNS) lesions result from perivascular immune cell infiltration associated with damage to myelin, oligodendrocytes and neurons. CNS autoimmunity and its regulation are dominated by the inflammatory cytokines IL17 and IFNγ, and the opposing regulatory cytokines IL10 and the type I IFNs. Toll-like receptors (TLR) play a critical role in modulating cytokine and chemokine secretion in response to exogenous Pathogen Associated to Molecular Patterns and endogenous Danger-Associated to Molecular Patterns. Here, we systematically examine the evidence that TLR play a major role in the initiation disease, the triggering of relapses, and regulation of CNS damage. Data from human studies are supported analyses of a variety of animal models, including Experimental Autoimmune Encephalomyelitis in TLR-deficient mice.