Atrial fibrillation (AF) is a potentially serious health risk, both because of its symptoms and because of its association with an increased risk for heart failure, hospitalization, thromboembolism, and death. Chapter 2 discusses selection of appropriate treatments and when to initiate these therapies. Older trials focused on comparing rate versus rhythm control treatment options for AF. It is now recognized that both rate and rhythm control are important and can be used together. This chapter reviews the historical, pivotal rate versus rhythm control trials that failed to show any overall survival benefit of rhythm over rate control, as well as the trials’ now-recognized limitations with respect to modern therapy. In addition, an in-depth discussion of the more recent trials of antiarrhythmic drugs (AAD) and ablation techniques (which have become available since the original rate versus rhythm trials were performed) is included. These updated trials show that when applied to patient- and disease-specific situations, rhythm control can reduce the risk for mortality and hospitalization. The chapter also reviews the guidelines that have been developed to achieve these goals. Chapter 2 is summarized as follows: (1) Rate control is needed (at rest and during exertion) to reduce rate-related symptoms when rhythm control is ineffective or incomplete and to prevent a tachycardia-induced cardiomyopathy. (2) Previous trials with pharmacological therapy alone comparing rate versus rhythm control using the AADs available at that time failed to show any overall survival benefit of rhythm control over rate control. (3) These earlier trials had many methodological limitations and enrolled participants who did not have access to modern therapies. (4) Newer therapies, including those for stroke prevention, dronedarone (the latest approved AAD), and AF ablation, have improved the safety and efficacy of rhythm control strategies.