Catecholamines exert physiologically important effects on the electrical properties and mechanical performance of the heart through the activation of adrenergic receptors. It has been 50 years since Ahlquist1 first postulated that the excitatory and inhibitory pressor responses to catecholamines must be mediated by distinct adrenergic receptors (ARs), then designated(for excitatory) and(for inhibitory). Ahlquist’s classification was expanded further by Lands et al, 2 who recognized that both-and-ARs could be conveniently categorized into 2 distinct subtypes on the basis of their relative potencies for ligands available at that time. In the ensuing years, the predominant AR expressed by cardiomyocytes was shown to conform to the 1-AR subtype. Our understanding of the molecular basis for sympathetic modulation was advanced further by the observations that under normal physiological conditions catecholamines induce positive inotropic, chronotropic, and lusitropic (relaxant) responses in the heart through a 1-AR–activated pathway, which involves the stimulatory GTP regulatory protein (Gs), activation of adenylyl cyclase (AC), accumulation of cAMP, stimulation of cAMP-dependent protein kinase A (PKA), and phosphorylation of key target proteins (including the L-type calcium channel [ICa, L], phospholamban [PLB], and troponin I [TNI]). Potential contributions of other AR subtypes to the mechanism (s) of catecholamine action in the heart were largely ignored in early studies. However, the traditional notion that only 1-ARs support cardiac contractile function has been challenged by recent research demonstrating that cardiac myocytes also express 2-ARs that link to important changes in cardiac contractile function. Although these 2-AR–dependent signals may represent only a relatively minor component of catecholamine responsiveness under normal physiological conditions, 2-ARs assume increased importance as a mechanism for inotropic support in the failing or aged heart, where there is a selective downregulation of