A variety of G protein-coupled receptors (GPCRs) are involved in the regulation of cardiovascular function. The β-adrenoceptors (β-ARs), with three subtypes, are the dominant receptor species in the heart, in which the β₁-AR and the β₂-AR are considered functional. Stimulation of the β-ARs produces myocardial inotropy via activation of the G_s-cAMP-PKA signaling cascade. Prolonged stimulation of the β₁-AR is cardiac harmful because the stimulated β₁-AR couples only to G_s proteins and it mediates a cardiotoxic signal. On the other hand, the β₂-AR couples dually to both G_s and G_i proteins and the β₂-AR-G_i pathway is antiapoptotic. The activated G_i signal also counteracts the β-AR-G_s-promoted positive inotropic effect. Other key players in cardiac β-AR signaling include Ca²⁺/calmodulin-dependent protein kinases (CaMKs), GPCR kinases (GRKs), β-arrestins and phosphodiesterases. During heart failure, excessive sympathetic stimulation results in the activation of the cardiotoxic β₁-AR-CaMKIIδ pathway and the upregulation of GRK2 and G_i in the heart. GRK2 promotes the desensitization of β-ARs and enhances a β₂-AR-mediated G_i signaling. These signal transduction processes accompanying the downregulation of the β₁-AR are involved in cardiac dysfunction, maladaptive cardiac remodeling, and the progression of chronic heart failure. β-Blockers are widely used in the treatment of cardiovascular disease. They have established their position as one of the “four pillars of heart failure” thirty years ago. In the present review, we provide an overview of the recent progress in the basic research of GPCRs focusing on cardiac β-AR signal transduction.