beta-adrenergic signaling plays a central role in the neurohumoral regulation of the heart and the progression of heart failure. Initially thought to be a simple linear cascade, this complex network is now recognized to utilize cross-talk with numerous other pathways, spatial compartmentation, and feedback control to coordinate cardiac electrophysiology, contractility, and adaptive remodeling. Here, we review recent basic insights and novel quantitative approaches that are leading to a more comprehensive understanding of beta-adrenergic signaling and thus motivate new therapeutic strategies for cardiac disease.