The Class III antiarrhythmic drugs have been used for the treatment of atrial fibrillation (AF); however, each has specific electrophysiologic properties that delineate different safety and/or effectiveness profiles. First-generation Class III agents seem to be more effective in preventing recurrence of AF than in converting AF to sinus rhythm. The high incidence of major cardiac and noncardiac side effects in the long term often requires discontinuation of the chronic antiarrhythmic therapy. The second-generation Class III drugs, ibutilide and dofetilide, have demonstrated interesting clinical applications, especially in the setting of atrial flutter. However, their favorable antiarrhythmic effect is counterbalanced by the high incidence of severe proarrhythmias. New promising experimental data suggest that the new Ikr-ks blockers may be free from these dangerous limitations, thus extending the indication of Class III drugs in the treatment of AF.