Pharmacological treatment of atrial fibrillation has been limited by the side effects and relative ineffectiveness of antiarrhythmic agents. Despite advances in nonpharmacological therapies, antiarrhythmic drugs continue to be used with the majority of patients who require treatment. More effective agents are being sought, and several approaches have been taken to develop effective agents with less toxicity. Modification of the amiodarone molecule has led to the development of agents such as dronedarone, a drug that preserves the activity of the original molecule while improving safety and simplifying the kinetics. Another approach is modulation of ion channels that are unique to atrial myocytes, to avoid ventricular proarrhythmia. As new and improved agents become available, the relative benefit of maintaining sinus rhythm over a rate control strategy may need to be reconsidered.