β-Adrenoceptor stimulation serves as the most powerful means to increase cardiac output in response to stress or exercise. However, sustained β-adrenoceptor stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy and apoptosis, thus contributing to heart failure. Coexisting cardiac β-adrenoceptor subtypes, mainly β₁-adrenoceptors and β₂-adrenoceptors, activate different signaling cascades with β₁-adrenoceptors coupling to G_s and β₂-adrenoceptors coupling to G_s and G_i pathways. As a result, sustained β₂-adrenoceptor stimulation protects cardiomyocytes against apoptosis via a G_i–phosphatidylinositol 3-kinase–protein kinase B pathway, whereas chronic β₁-adrenoceptor stimulation induces myocyte hypertrophy and apoptosis by protein kinase A-independent activation of calmodulin kinase II signaling. These advances in our understanding of β-adrenoceptor subtype signaling identify the mechanisms that underlie the beneficial effects of β-adrenoceptor antagonists and delineate the rationale for combining β₁-adrenoceptor blockade with β₂-adrenoceptor activation as a potential therapy for heart failure.