The beta-adrenergic receptor signaling system plays a fundamental role in heart function. Signaling through beta ARs can be dampened by the actions of the beta AR kinase, a kinase whose expression and activity are elevated in chronic human heart failure. In this review we highlight studies that have used genetically engineered mice to understand how perturbations in myocardial beta AR signaling could adversely impact the pathogenesis of cardiac disease. Interrupting this process may provide novel therapeutic strategies in the treatment of human heart failure.