Recent studies have added complexities to the conceptual framework of cardiac &bgr;-adrenergic receptor (&bgr;-AR) signal transduction. Whereas the classical linear Gs–adenylyl cyclase–cAMP–protein kinase A (PKA) signaling cascade has been corroborated for &bgr;1-AR stimulation, the &bgr;2-AR signaling pathway bifurcates at the very first postreceptor step, the G protein level. In addition to Gs, &bgr;2-AR couples to pertussis toxin–sensitive Giproteins, Gi2and Gi3. The coupling of &bgr;2-AR to Giproteins mediates, to a large extent, the differential actions of the &bgr;-AR subtypes on cardiac Ca2+handling, contractility, cAMP accumulation, and PKA-mediated protein phosphorylation. The extent of Gicoupling in ventricular myocytes appears to be the basis of the substantial species-to-species diversity in &bgr;2-AR–mediated cardiac responses. There is an apparent dissociation of &bgr;2-AR–induced augmentations of the intracellular Ca2+(Cai) transient and contractility from cAMP production and PKA-dependent cytoplasmic protein phosphorylation. This can be largely explained by Gi-dependent functional compartmentalization of the &bgr;2-AR–directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during &bgr;-AR subtype stimulation. Emerging evidence also points to distinctly different roles of these &bgr;-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specificity of &bgr;-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of &bgr;-AR subtypes in healthy and diseased hearts.