Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), which is considered immune-mediated. Our knowledge of innate immune mechanisms in the CNS and their implications for pathogenesis and treatment of multiple sclerosis (MS) are limited, particularly if compared with the body of literature on adaptive immune mechanisms. There is, however, growing understanding of the workings of the innate immune system and accordingly, of its potential role in driving immune-mediated pathology. Such mechanisms will be discussed in this review along with potential therapeutic opportunities. These may require blocking pathogenic innate immunity and in some cases, promoting its protective effects.