Presently available drugs used for atrial fibrillation (AF) therapy have major limitations (moderate efficacy and increased risk of potentially life-threatening proarrhythmia), making new drug developments crucial. Novel drugs like the multichannel blocker dronedarone have the potential to convert AF to prevent AF-related stroke and to reduce cardiovascular morbidity and mortality, opening new directions for innovative antiarrhythmic options. Here we summarize mechanistic evidence for atrial-selective sodium channel block as anti-AF principle putting it into perspective to the work by Bogdan et al. 2011, which demonstrated stronger sodium current inhibition by dronedarone at depolarized potentials resulting in atrial selectivity. We also discuss pertinent facts about remodeling processes induced by and leading to AF which likely explain why pharmacological cardioversion is effective in very early stages of AF only.Atrial selectivity of sodium channel block is a novel anti-AF approach that exploits atrial-ventricular differences in sodium current properties (more negative half-inactivation in atria) and in resting membrane potential (more positive in atria leaving a greater proportion of sodium channels in the inactivated state), leading to reduced atrial current availability at any given membrane potential. Therefore inactivated-state sodium channel blockers like dronedarone preferentially suppress atrial sodium currents, especially during rapid atrial rhythms like in AF. However, dronedarone less effectively terminates AF compared to amiodarone having only a moderate overall efficacy. Much more work is needed to precisely define the contribution of atrial-selective sodium current inhibition for dronedarone's overall anti-AF efficacy.AF is an increasing health problem and is associated with substantial cardiovascular morbidity and mortality, with stroke representing the most critical complication. Presently available drugs used for therapy of AF (antiarrhythmic drugs and anticoagulants) have major limitations because of moderate efficacy and inherent risk of potentially life-threatening proarrhythmia or bleeding complications, making new drug developments crucial (Dobrev and Nattel 2010). Novel drugs like dronedarone have the potential to prevent AF-related stroke and to reduce cardiovascular morbidity and mortality ), opening a new avenue for innovative antiarrhythmic options.In January 2010 dronedarone has been approved for the treatment of nonpersistent AF in Europe. It is an antiarrhythmic compound with rate-and rhythm-controlling properties, which has been developed as a structurally related, multichannelblocking congener of amiodarone with a similarly broad spectrum of inhibitory actions on ion channels (Ehrlich and Nattel 2009). In the April issue of Naunyn-Schmiedeberg's Archive of Pharmacology, Bogdan and colleagues (2011) illustrate the mode of dronedarone action on sodium channels and identify a peculiar behavior of the substance to inhibit inactivated channels at more depolarized potentials more effe...