We have recently developed a new and robust “chemogenetic” animal model of heart failure that is based on a central feature of heart failure in humans: an increase in redox stress in the heart. Our chemogenetic approach exploits a recombinant yeast enzyme that can be activated in vivo to generate hydrogen peroxide in cardiac myocytes, leading to dilated cardiomyopathy. In these studies, we show that chemogenetic heart failure is associated with striking changes in the cardiac metabolome and transcriptome that share many features with human heart failure and with other preclinical models of heart failure. These observations help to validate the chemogenetic approach as an informative animal model for the discovery of novel therapeutic targets for the prevention and treatment of heart failure.