β-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 β-adrenergic receptor (β-AR) signaling and cardiac function. Furthermore, there are pathophysiologic alterations in the expression and regulation of proteins that are regulated by β-ARs during HF. Analyses of these complex signaling pathways have led to a better understanding of HF mechanisms and the use of β-adrenergic antagonists, which have notably altered HF-related morbidity and mortality. Despite therapeutic advances that have affected β-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 β-adrenergic signal-transduction pathways, the best-described β-AR polymorphisms, and therapies that target the β-AR pathway in HF.