In both physiologic and pathological conditions, instantaneous heart rate value is the result of a rather complex interplay. It constantly varies under the influence of a number of factors: nonmodifiable and modifiable ones. Pharmacologic blockade with beta-adrenergic antagonists and/or with parasympathetic antagonists such as atropine have permitted the identification of the mechanisms of autonomic nervous regulation of heart rate in a variety of physiologic and pathological conditions. The analysis of heart rate and blood pressure variability has yielded additional information on the autonomic control of the circulation, which has proven to have diagnostic and prognostic implications in a number of clinically relevant conditions such as hypertension, acute myocardial infarction, heart failure, and predisposition to sudden cardiac death. This article will summarize, based on available epidemiologic and clinical studies, the key variables influencing heart rate and heart rate variability in view of the known association between heart rate and cardiovascular disease.