Classical ligand-activated βARs enhance cardiac contractility by coupling to G_s, formation of cAMP by adenylyl cyclase (AC), and PKA-dependent phosphorylation of various target proteins (e.g., ryanodine receptor [RyR]; phospholamban [PLN], troponin I [TnI], and the L-type Ca²⁺ channel [LTCC]). Chronic β₁AR stimulation is detrimental and induces cardiomyocyte hypertrophy and apoptosis. In this issue of the JCI, Noma et al. (10) have delineated a novel signaling pathway leading to GRK- and β-arrestin–dependent Src-kinase (SRC) and MMP activation. MMP activation in turn sheds HB-EGF from the cell surface, and this serves as a ligand for cardiomyocyte EGFRs, which mediate ERK/MAPK activation. This pathway protects from β₁AR-induced cardiomyocyte apoptosis but has been associated with cardiac hypertrophy.