The anti-arrhythmic efficacy of the late sodium channel current (late I_Na) inhibition has been convincingly demonstrated in the ventricles, particularly under conditions of prolonged ventricular repolarization. The value of late I_Na block in the setting of atrial fibrillation (AF) remains poorly investigated. All sodium channel blockers inhibit both peak and late I_Na and are generally more potent in inhibiting late vs. early I_Na. Selective late I_Na block does not prolong the effective refractory period (ERP), a feature common to practically all anti-AF agents. Although the late I_Na blocker ranolazine has been shown to be effective in suppression of AF, it is noteworthy that at concentrations at which it blocks late I_Na in the ventricles, it also potently blocks peak I_Na in the atria, thus causing rate-dependent prolongation of ERP due to development of post-repolarization refractoriness. Late I_Na inhibition in atria is thought to suppress intracellular calcium (Ca_i)-mediated triggered activity, secondary to a reduction in intracellular sodium (Na_i). However, agents that block late I_Na (ranolazine, amiodarone, vernakalant, etc) are also potent atrial-selective peak I_Na blockers, so that the reduction of Na_i loading in atrial cells by these agents can be in large part due to the block of peak I_Na. The impact of late I_Na inhibition is reduced by the abbreviation of the action potential that occurs in AF patients secondary to electrical remodeling. It stands to reason that selective late I_Na block may contribute more to inhibition of Ca_i-mediated triggered activity responsible for initiation of AF in clinical pathologies associated with a prolonged atrial APD (such as long QT syndrome). Additional studies are clearly needed to test this hypothesis.