Development of cardiac hypertrophy and progression to heart failure entails profound changes in myocardial metabolism, characterized by a switch from fatty acid utilization to glycolysis and lipid accumulation. We report that hypoxia-inducible factor (HIF)1α and PPARγ, key mediators of glycolysis and lipid anabolism, respectively, are jointly upregulated in hypertrophic cardiomyopathy and cooperate to mediate key changes in cardiac metabolism. In response to pathologic stress, HIF1α activates glycolytic genes and PPARγ, whose product, in turn, activates fatty acid uptake and glycerolipid biosynthesis genes. These changes result in increased glycolytic flux and glucose-to-lipid conversion via the glycerol-3-phosphate pathway, apoptosis, and contractile dysfunction. Ventricular deletion of Hif1α in mice prevents hypertrophy-induced PPARγ activation, the consequent metabolic reprogramming, and contractile dysfunction. We propose a model in which activation of the HIF1α-PPARγ axis by pathologic stress underlies key changes in cell metabolism that are characteristic of and contribute to common forms of heart disease.