Enhanced understanding of the mechanisms underlying atrial fibrillation (AF) and advent of catheter-based therapy for AF has altered the approach to patients with this most common arrhythmia. However, despite the success of aggressive procedural techniques, pharmacologic therapy remains the first-line and mainstay approach in the treatment of AF. This review of new antiarrhythmic drug (AAD) therapy for AF provides an in-depth overview of recently available classic and new investigational drugs being considered for AF treatment. Currently available AADs are associated with less than satisfactory efficacy in preventing AF and a significant side effect profile, including ventricular proarrhythmia. Recent investigations have focused on development of new AADs that, hopefully, will be more effective and safer even in patients with structural heart disease. These new AADs include selective multi-ion channel and atrial specific blockers and agents that target the underlying etiologies and substrate alterations that lead to AF. Included among the latter new category are agents that suppress activation of the renin-angiotensin-aldosterone system or inflammation, which represent novel targets for drug therapy for AF. Finally, new selective A1 adenosine receptor agonists may offer the possibility of more specific and successful ventricular rate control during AF. There is considerable hope and interest that improved understanding of AF mechanisms ultimately will result in more effective and less dangerous pharmacologic therapy becoming available in the future.