Atrial fibrillation (AF) is a common disorder that significantly impacts the lives of affected patients. The restoration of sinus rhythm may prevent AF progression and reduce the occurrence of negative sequelae; however, available antiarrhythmic drugs (AADs) have largely failed to demonstrate significant benefit relative to rate control with respect to morbidity and mortality outcomes. The review commentary will address current knowledge regarding the pathologic mechanisms of AF, current trials that investigate rate and rhythm strategies, and future therapies that may change treatment approaches based on preliminary evidence suggesting a more favorable safety profile. The observed outcomes are likely a reflection of the limited efficacy plus poor safety and tolerability of available AADS. However, data from patients who attained and maintained sinus rhythm in a number of clinical studies demonstrate that the achievement of normal sinus rhythm can indeed reduce AF-associated morbidity and mortality. Furthermore, the results of trials designed to assess specific morbidity and mortality outcomes such as cardiovascular death hospitalization suggest that the development of safer AF therapies, whether pharmacologic or nonpharmacologic, can potentially improve clinical outcomes.