There is increasing evidence that single site atrial pacing is beneficial for atrial fibrillation (AF) prevention in sick sinus syndrome. Multisite atrial pacing methods such as dual site right atrial pacing and biatrial synchronous pacing are currently under active evaluation for AF and atrial flutter prevention in patients with or without bradyarrhythmias. Clinical studies have demonstrated that multisite atrial pacing has an incremental benefit as compared with single site right and left atrial pacing. The electrophysiologic rationale for the efficacy of multisite atrial pacing is based on the reduction of global and local atrial activation times during pacing and for closely coupled atrial premature beats. This results in earlier recovery of excitability and decreased conduction delay. Dual site right atrial pacing consisting of simultaneous pacing from the high right atrium and the coronary sinus ostium reduces the activation times in virtually all left and right atrial regions, especially in areas of conduction delay. Multisite pacing methods reduce the ability to initiate AF with atrial premature beats by reducing the window for AF induction and minimizing the dispersion of atrial refractoriness. In our long-term clinical experience including 30 patients with paroxysmal and chronic drug-refractory AF, 78% of the patients were free of AF recurrence at 1 year, 63% at 2 years, and 56% at 3 years. Rhythm control was achieved in 86% of patients during a follow-up period of 3 years. Concomitantly, we observed a marked reduction in need for anticoagulation, type I antiarrhythmic drugs, and cardioversion therapies. There were no coronary sinus lead-related complications during follow-up. After the initial favorable clinical experiences, two major prospective randomized trials (DAPPAF and SYNBIAPACE) are under way in North America and Europe to evaluate quantitatively the beneficial impact of multisite atrial pacing for AF prevention.