There are many factors that influence drug block of voltage-gated Na+ channels (VGSC). Pharmacological agents vary in conformation, charge, and affinity. Different drugs have variable affinities to VGSC isoforms, and drug efficacy is affected by implicit tissue properties such as resting potential, action potential morphology, and action potential frequency. The presence of polymorphisms and mutations in the drug target can also influence drug outcomes. While VGSCs have been therapeutic targets in the management of cardiac arrhythmias, their potential has been largely overshadowed by toxic side effects. Nonetheless, many VGSC blockers exhibit inherent voltage- and use-dependent properties of channel block that have recently proven useful for the diagnosis and treatment of genetic arrhythmias that arise from defects in Na+ channels and can underlie idiopathic clinical syndromes. These defective channels suggest themselves as prime targets of disease and perhaps even mutation specific pharmacological interventions.