The effective and safe treatment of pain is an unmet health-care need. Current medications used for pain management are often only partially effective, carry dose-limiting adverse effects and are potentially addictive, highlighting the need for improved therapeutic agents. Most common pain conditions originate in the periphery, where dorsal root ganglion and trigeminal ganglion neurons feed pain information into the CNS. Voltage-gated sodium (Na) channels drive neuronal excitability and three subtypes – Na1.7, Na1.8 and Na1.9 – are preferentially expressed in the peripheral nervous system, suggesting that their inhibition might treat pain while avoiding central and cardiac adverse effects. Genetic and functional studies of human pain disorders have identified Na1.7, Na1.8 and Na1.9 as mediators of pain and validated them as targets for pain treatment. Consequently, multiple Na1.7-specific and Na1.8-specific blockers have undergone clinical trials, with others in preclinical development, and the targeting of Na1.9, although hampered by technical constraints, might also be moving ahead. In this Review, we summarize the clinical and preclinical literature describing compounds that target peripheral Na channels and discuss the challenges and future prospects for the field. Although the potential of peripheral Na channel inhibition for the treatment of pain has yet to be realized, this remains a promising strategy to achieve non-addictive analgesia for multiple pain conditions.