Pain serves a crucial physiological function, warning the body of impending or actual tissue damage, preventing further damage and aiding the healing process. Neuropathic pain, resulting from nervous system injury or dysfunction, can be a serious medical problem and especially difficult to treat. Although sodium channel blockers are clinically useful for treating pain, they often provide only partial relief and adverse effects associated with nonspecific actions can limit their use. Research on the roles of sodium channels in neuronal excitability and pain shows that specific sodium channel isoforms are crucial determinants of nociception and neuropathic pain, indicating that it should be possible to develop sodium channel blockers with lower toxicity and enhanced efficacy for treating neuropathic pain.