Toll-like receptors (TLRs) are germline-encoded pattern-recognition receptors that initiate innate immune responses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns (PAMPs). After tissue injury or cellular stress, TLRs also detect endogenous ligands known as danger-associated molecular patterns (DAMPs). TLRs are expressed in both non-neuronal and neuronal cell types in the central nervous system (CNS) and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs (such as TLR2, TLR3, and TLR4) induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neuropathic pain. In particular, primary sensory neurons, such as nociceptors, express TLRs (e.g., TLR4 and TLR7) to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch. Toll-like receptors (TLRs) are germline-encoded pattern-recognition receptors that recognize inn inn immune receptors by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns (PAMPs). After tissue injury or cellular stress, TLRs also detect endogenous ligands known as danger-associated molecular patterns (DAMPs). TLRs are expressed in both non-neuronal and neuronal cell types in the central nervous system (CNS) and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs (such as TLR2, TLR3, and TLR4) induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neuropathic pain. In particular, primary sensory neurons, such as nociceptors, express TLRs (eg, TLR4 and TLR7) to sense exogenous PAMPs and endogenous DAMPs released after tissu e injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch.