Fundamental changes in nutrient metabolism underlie many disease processes, including obesity, diabetes, and cancer. Metabolic derangements are also a hallmark of heart disease, both in the context of failure and ischemia, and likely contributors to its etiology. For example, while the healthy heart favors fats as a fuel, failing hearts will consume more glucose; but it is unclear if this is pathological or protective. It is very likely that manipulation of metabolic pathways can affect, and possibly augment and protect, heart function. Yet no drug therapy exists that targets cardiac metabolism. Staples of ischemic disease management largely focus on anti-platelet, cholesterol-lowering, and beta-adrenergic blocking regimens. Heart failure medicines focus on maladaptive neuro-hormonal responses, a strategy several decades old. Our goal here is to delineate exactly how critical aspects of metabolism are altered in cardiac ischemia, and to identify new targets of pharmacological intervention. Metabolism largely remains unexplored because of its intricate network of regulation, compounded by the fact that variations in this network will often escape traditional methods of gene expression profiling. But by using high throughput metabolomic and proteomic platforms, we have striking evidence that the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is instrumental in the heart’s response to ischemia. Dynamic, real-time metabolomic flux using heavy carbon isotope labeling points toward a partial shift of glycolytic intermediates toward lipid synthesis during ischemic stress in cardiomyocytes, precisely at the step catalyzed by GAPDH. Expansive phospho-proteomic analyses from Langendorff ex vivo hanging heart experiments show that this shift in metabolism may be triggered by an inhibitory phosphorylation of GAPDH. Our hypothesis that glycolysis is in part rerouted toward triglyceride synthesis is a revolutionary departure from decades-old perceptions of energy management. Modulating GAPDH function, either directly or indirectly via partner proteins, may offer insight into untapped areas of therapy. Our early attempts with chemicals that inhibit GAPDH already show heart cells with improved survival under ischemia.