Beta-adrenergic signaling is an important regulator of myocardial function. During the progression of heart failure (HF), a reproducible series of biochemical events occurs that affects beta-adrenergic receptor (beta-AR) signaling and cardiac function. Furthermore, there are pathophysiologic alterations in the expression and regulation of proteins that are regulated by beta-ARs during HF. Analyses of these complex signaling pathways have led to a better understanding of HF mechanisms and the use of beta-adrenergic antagonists, which have notably altered HF-related morbidity and mortality. Despite therapeutic advances that have affected beta-AR signaling, HF remains a leading cause of hospitalization and a principal cause of death in industrialized nations. In this review, we summarize current insights into beta-adrenergic signal-transduction pathways, the best-described beta-AR polymorphisms, and therapies that target the beta-AR pathway in HF.