Neuropathic pain is a maladaptive response of the nervous system to damage, characterized by spontaneous and amplified pain in response to noxious and innocuous stimuli. This pain results from alterations in the somatosensory nervous system, including ectopic action potential generation, synaptic facilitation and disinhibition, loss of synaptic connectivity, and neuroimmune interactions. While neural lesions are necessary, they are not sufficient for neuropathic pain, as genetic polymorphisms, gender, and age also influence the risk of developing persistent pain. Treatment strategies should aim to prevent maladaptive plasticity and reduce intrinsic risk, rather than merely suppressing symptoms. The article reviews the neurobiological mechanisms underlying neuropathic pain, including peripheral and central sensitization, ectopic impulse generation, disinhibition, structural changes, neurodegeneration, and neuro-immune interactions. It also discusses the challenges in translating preclinical findings to clinical practice and the need for a standardized classification of pain phenotypes to improve treatment outcomes. Genetic determinants of neuropathic pain are explored, highlighting the potential for identifying molecular mechanisms and therapeutic targets.Neuropathic pain is a maladaptive response of the nervous system to damage, characterized by spontaneous and amplified pain in response to noxious and innocuous stimuli. This pain results from alterations in the somatosensory nervous system, including ectopic action potential generation, synaptic facilitation and disinhibition, loss of synaptic connectivity, and neuroimmune interactions. While neural lesions are necessary, they are not sufficient for neuropathic pain, as genetic polymorphisms, gender, and age also influence the risk of developing persistent pain. Treatment strategies should aim to prevent maladaptive plasticity and reduce intrinsic risk, rather than merely suppressing symptoms. The article reviews the neurobiological mechanisms underlying neuropathic pain, including peripheral and central sensitization, ectopic impulse generation, disinhibition, structural changes, neurodegeneration, and neuro-immune interactions. It also discusses the challenges in translating preclinical findings to clinical practice and the need for a standardized classification of pain phenotypes to improve treatment outcomes. Genetic determinants of neuropathic pain are explored, highlighting the potential for identifying molecular mechanisms and therapeutic targets.