Heart rate is a precisely regulated variable, which plays a critical role in health and disease. Numerous epidemiologic studies and large post-myocardial infarction trials have provided evidence that elevated resting heart rate is an independent risk factor for cardiac mortality. This body of knowledge has prompted the development and evaluation of negative chronotropic agents, prototypically the I(f) inhibitor Ivabradine. The present review addresses several fundamental questions: (1) How is heart rate regulated at the integrative, cellular, and molecular levels? (2) How are autonomic tone and reflexes measured clinically, and what is the prognostic utility of these parameters? (3) What mechanisms are responsible for the cardiovascular pathology associated with elevated heart rates? (4) Does reducing heart rate independent of effects on other factors protect against cardiovascular events?