Painful neuropathies are frequently encountered in clinical practice as an early or late complication of several systemic disorders. Among them, diabetes is one of the most important due to its epidemiology and the relevance for regulatory agencies in the assessment of efficacy of new analgesics. However, the presentation and course of painful neuropathies, as well as the response to available drugs, are highly variable and unpredictable, posing significant challenges in the management of patients. Experimental and clinical studies have suggested that polymorphisms and mutations in pain-related genes are involved in the facilitation or inhibition of nociception, and might modulate neuropathic pain and the response to analgesics in patients. Voltage-gated sodium channel genes are among the most relevant, due to the key role of these membrane proteins in the physiology of nociception and their involvement in the pathogenesis of idiopathic painful small fiber neuropathies. These compelling features make sodium channel candidate targets for a novel approach to painful diabetic and idiopathic neuropathies, which will hopefully allow a new classification of patients and more effective targeted treatments.