—Recent studies have added complexities to the conceptual framework of cardiac β-adrenergic receptor (β-AR) signal transduction. Whereas the classical linear G_s–adenylyl cyclase–cAMP–protein kinase A (PKA) signaling cascade has been corroborated for β₁-AR stimulation, the β₂-AR signaling pathway bifurcates at the very first postreceptor step, the G protein level. In addition to G_s, β₂-AR couples to pertussis toxin–sensitive G_i proteins, G_i2 and G_i3. The coupling of β₂-AR to G_i proteins mediates, to a large extent, the differential actions of the β-AR subtypes on cardiac Ca²⁺ 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 β₂-AR–mediated cardiac responses. There is an apparent dissociation of β₂-AR–induced augmentations of the intracellular Ca²⁺ (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 β₂-AR–directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during β-AR subtype stimulation. Emerging evidence also points to distinctly different roles of these β-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specificity of β-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of β-AR subtypes in healthy and diseased hearts.