Atrial fibrillation (AF) is the most common clinical arrhythmia and one of the most important factors for ischemic stroke. In general, AF is treated with "channel-blocking drugs" to restore sinus rhythm and warfarin is recommended in the majority of patients to prevent atrial thrombus formation and thromboembolic events. In the recent years, a tremendous amount has been learned about the pathophysiology and molecular biology of AF. Thus, pharmacologic interference with specific signal transduction pathways with "non-channel-blocking drugs" appears promising as a novel antiarrhythmic approach to maintain sinus rhythm and to prevent atrial clot formation. Therefore, this review will highlight some novel "nonchannel drug targets" for AF therapy.