Toll-like receptors (TLRs) enable mammalian cells to sense pathogenic challenges. They are essential for appropriate initiation, execution and regulation of innate and adaptive immune responses. Whereas TLR-mediated processes in the central nervous system (CNS) might contribute to detrimental (auto)immune reactions, they are unlikely to have exclusively neurodestructive consequences. Indeed, appropriately controlled TLR signaling might be crucial for preserving CNS structure and function in certain contexts. Recent findings illustrate neuroprotective capacities for TLRs, mediated by containment of trauma-associated infection or by recruitment of neuroprotective T lymphocytes. By the latter mechanism, endogenous or therapeutically administered TLR ligands could conceivably generate neuroprotective benefits in noninfectious CNS disorders. This article focuses on the yet less-addressed protective potential of TLR engagement within the CNS.