The stimulation of β-adrenergic receptor (βAR) plays a pivotal role in regulating myocardial function and morphology in the normal and failing heart. Three genetically and pharmacologically distinct βAR subtypes, β₁AR, β₂AR, and β₃AR, are identified in various types of cells. While both β₁AR and β₂AR, the predominant βAR subtypes expressed in the heart of many mammalian species including human, are coupled to the G_s–adenylyl cyclase–cAMP–PKA pathway, β₂AR dually activates pertussis toxin-sensitive G_i proteins. During acute stimulation, β₂AR–G_i coupling partially inhibits the G_s-mediated positive contractile and relaxant effects via a G_i–G_βγ–phosphoinositide 3-kinase (PI3K)-dependent mechanism in adult rodent cardiomyocytes. More importantly, persistent β₁AR stimulation evokes a multitude of cardiac toxic effects, including myocyte apoptosis and hypertrophy, via a calmodulin-dependent protein kinase II (CaMKII)-, rather than cAMP–PKA-, dependent mechanism in rodent heart in vivo and cultured cardiomyocytes. In contrast, persistent β₂AR activation protects myocardium by a cell survival pathway involving G_i, PI3K, and Akt. In this review, we attempt to highlight the distinct functionalities and signaling mechanisms of these βAR subtypes and discuss how these subtype-specific properties of βARs might affect the pathogenesis of congestive heart failure (CHF) and the therapeutic effectiveness of certain β-blockers in the treatment of congestive heart failure.