Innate pattern recognition receptors are implicated in first-line defense against pathogens but also participate in maintenance of tissue homeostasis and response to injury. This chapter reviews the role of Toll-like receptors (TLRs) in neuronal and glial responses that are associated with neurodegeneration. Accompanying roles for infection and inflammation, involvement in clinical neurodegenerative disorders, and heterogeneity of glial response are discussed. A “strength of signal” hypothesis is advanced in an attempt to reconcile evolutionarily selected and therefore likely beneficial effects of TLR signaling in the nervous system with capability for neurotoxocity and gliotoxicity.