Despite advances in treatment, atrial fibrillation (AF) remains the most common arrhythmia in humans. Antiarrhythmic drug therapy continues to be a cornerstone of AF treatment, even in light of emerging non-pharmacologic therapies. Conventional antiarrhythmic drugs target cardiac ion channels and are often associated with modest AF suppression and the risk of ventricular proarrhythmia. Ongoing drug development has focused on targeting atrial-specific ion channels as well as novel non-ionic targets. Targeting non-ionic mechanisms may also provide new drugs directed towards the underlying mechanisms responsible for AF and possibly greater antiarrhythmic potency. Agents that act against these new targets may offer improved safety and efficacy in AF treatment.