Parasite infections in the central nervous system (CNS) are a major cause of morbidity and mortality worldwide, second only to HIV infection. Finding appropriate therapeutic measures to control CNS parasite infections requires an understanding of the tissue-specific host response. CNS parasitic diseases are invariably associated with persistent T-helper 1 (Th1) cytokine-dependent proinflammatory responses. Although type 1 cytokine-dependent proinflammatory responses are essential to control several types of parasite infections, their persistent production contributes to the development of neuropathology with severe consequences. A family of proteins called Toll-like receptors (TLRs) plays a pivotal role in the induction of inflammatory cytokines during infections and tissue injury. Accumulating evidence indicates that in several CNS parasitic infections such as toxoplasmosis and sleeping sickness, host responses mediated through TLRs contribute to parasite clearance and host survival. However, TLR-mediated responses can also contribute to disease severity, as exemplified in cerebral malaria, neurocysticercosis and river blindness. Thus, TLRs influence the immunopathogenesis of CNS parasitic infections by mechanisms that can either benefit the host or further contribute to CNS pathology. This chapter discusses the immunopathogenesis of parasitic infections in the CNS and the role of TLRs in this process.