Recent studies have added complexities to the conceptual framework of cardiac beta-adrenergic receptor (beta-AR) signal transduction. Whereas the classical linear G(s)-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling cascade has been corroborated for beta(1)-AR stimulation, the beta(2)-AR signaling pathway bifurcates at the very first postreceptor step, the G protein level. In addition to G(s), beta(2)-AR couples to pertussis toxin-sensitive G(i) proteins, G(i2) and G(i3). The coupling of beta(2)-AR to G(i) proteins mediates, to a large extent, the differential actions of the beta-AR subtypes on cardiac Ca(2+) handling, contractility, cAMP accumulation, and PKA-mediated protein phosphorylation. The extent of G(i) coupling in ventricular myocytes appears to be the basis of the substantial species-to-species diversity in beta(2)-AR-mediated cardiac responses. There is an apparent dissociation of beta(2)-AR-induced augmentations of the intracellular Ca(2+) (Ca(i)) transient and contractility from cAMP production and PKA-dependent cytoplasmic protein phosphorylation. This can be largely explained by G(i)-dependent functional compartmentalization of the beta(2)-AR-directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during beta-AR subtype stimulation. Emerging evidence also points to distinctly different roles of these beta-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specificity of beta-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of beta-AR subtypes in healthy and diseased hearts.