Despite improvements in the treatment of cardiovascular diseases, the prognosis of heart failure remains poor. To identify potential novel therapeutic targets, Tsuda et al. analyzed G-protein-coupled receptor (GPCR) expression in mouse cardiomyocytes 2 weeks following transverse aortic constriction (TAC) and identified markedly increased expression of corticotropin-releasing hormone receptor 2 (CRHR2). Mice with cardiomyocyte-specific deletion of Crhr2 were protected from TAC-induced cardiac dysfunction, whereas mice treated with the CRHR2 antagonist antisauvagine-30, one week after TAC surgery, did not develop heart failure.