Background: In patients with atrial fibrillation (AF), ventricular rate control with medications has been found to be noninferior in preventing clinical events, compared to a strategy converting patients to sinus rhythm and maintaining it with medications. Guidelines have accepted rate control as an acceptable therapeutic option. Most of the prior studies excluded patients without significant left ventricular dysfunction, or permanent AF. Methods: The authors searched the PubMed, CENTRAL, and EMBASE databases for randomized controlled trials from 1966 to 2011. Trials included were direct head‐to‐head comparisons of rate‐ and rhythm‐control strategy using pharmacological means. The primary outcome assessed was risk of all‐cause mortality. We also assessed other pooled clinical endpoints using a random effects model (Mantel‐Haenszel) between rate and rhythm‐control strategies. Results: Ten studies (total N = 7,867) met inclusion/exclusion criteria. In‐hospital mortality was not different between groups (P = 0.31). The rates of stroke, systemic embolism, worsening heart failure, myocardial infarction, and bleeding were also similar. However, rates of rehospitalization were much lower with a rate‐control strategy (P = 0.007). An exploratory analysis in patients younger than 65 years revealed a rhythm‐control strategy was superior to rate control in the prevention of all‐cause mortality (P = 0.0007). Conclusions: This systematic review suggests no difference in clinical outcomes with a rate or rhythm‐control strategy with AF. However, rehospitalization rates appear to be lower with pharmacological rate control for all ages, while finding support for rhythm control in younger patients. (PACE 2013; 36:122–133)