Central sensitization is a phenomenon where nociceptive inputs trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, leading to pain hypersensitivity. This can manifest as dynamic tactile allodynia, punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. Central sensitization can be rapidly induced in human volunteers through various experimental noxious conditioning stimuli and results in secondary changes in brain activity detectable by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that suggest central sensitization plays a significant role in conditions such as fibromyalgia, osteoarthritis, musculoskeletal disorders, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders, and postsurgical pain. The comorbidity of these pain hypersensitivity syndromes, their similar clinical presentation, and response to centrally acting analgesics indicate a commonality in their pathophysiology. Research is ongoing to determine if there are individuals with a higher inherited propensity for developing central sensitization and if this increases the risk of developing conditions with pain hypersensitivity and their chronicity. Diagnostic criteria for central sensitization will aid in phenotyping patients for more effective treatments. Discovering genetic and environmental contributors to central sensitization and objective biomarkers will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent form of pain plasticity.Central sensitization is a phenomenon where nociceptive inputs trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, leading to pain hypersensitivity. This can manifest as dynamic tactile allodynia, punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. Central sensitization can be rapidly induced in human volunteers through various experimental noxious conditioning stimuli and results in secondary changes in brain activity detectable by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that suggest central sensitization plays a significant role in conditions such as fibromyalgia, osteoarthritis, musculoskeletal disorders, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders, and postsurgical pain. The comorbidity of these pain hypersensitivity syndromes, their similar clinical presentation, and response to centrally acting analgesics indicate a commonality in their pathophysiology. Research is ongoing to determine if there are individuals with a higher inherited propensity for developing central sensitization and if this increases the risk of developing conditions with pain hypersensitivity and their chronicity. Diagnostic criteria for central sensitization will aid in phenotyping patients for more effective treatments. Discovering genetic and environmental contributors to central sensitization and objective biomarkers will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent form of pain plasticity.