The traditional notion that catecholamine actions are mediated by the predominant β₁-adrenergic receptor (β₁-AR) subtype linked to the activation of adenylyl cyclase and the accumulation of cyclic adenosine 3′,5′-monophosphate (cAMP) in cardiomyocytes has been challenged by recent studies showing that cardiomyocytes co-express pharmacologically distinct β₂-AR subtypes that activate a more broad range of downstream effectors. While β₁- and β₂-ARs exert largely functionally equivalent cellular actions in heterologous expression systems, signaling by endogenous β-AR subtypes in highly differentiated cells such as cardiomyocytes can be strikingly different. There is growing evidence that certain features of the signaling phenotypes for β-AR subtypes in cardiomyocytes are inconsistent with traditional models that attribute signaling specificity to high-affinity protein–protein interactions between receptors, G-proteins, and effectors freely mobile on surface membranes. This chapter summarizes recent studies that focus on membrane microdomains (such as caveolae or lipid rafts) as sites that differentially localizing individual β-AR subtypes as well as the downstream signaling machinery that generates, propagates, and downregulates the cAMP–protein kinase A signaling pathway. To the extent that this mechanism calibrates β-AR responses in cardiomyocytes, it would be expected to be pertinent to the pathogenesis of heart failure, where chronic/persistent β-AR signaling contributes to ventricular remodeling and impacts on long-term survival.