SUMMARY Heart failure (HF) is a leading cause of death worldwide, and the leading cause of hospital admissions in patients over 65 in the US. The five-year mortality rate for patients with HF remains ~50%. Neurohormonal blockade has been the mainstay of HF management for decades, but the limits of its benefits have likely been reached. Novel therapies, addressing novel pathways, are direly needed. Mounting evidence indicates that the failing heart is an “engine out of fuel” that fails to use fuel appropriately to satisfy its metabolic demands. Understanding how the heart handles various fuels during health and disease, and finding ways to modulate these pathways, thus holds great promise as novel therapies, orthologous to current neurohormonal blockade. We focus here on branched chain amino acids (BCAAs). Plasma BCAA levels have been noted for decades to be elevated in heart failure, and often to predict adverse outcomes. The expression of BCAA catabolic genes is the most significantly suppressed signature in human failing hearts. Despite these observations, however, the role of BCAAs in heart failure remains poorly understood, and the therapeutic opportunities consequently remain ill-defined. For example, the extent to which BCAA consumption by the heart is required for normal or injured cardiac function is unknown. Similarly unknown is the role of BCAA catabolism in other tissues, in particular the skeletal muscle, which we have shown carries out the lion’s share of BCAA catabolism in the whole organism. Finally, comprehensive quantification of BCAA (and other metabolite) consumption in human hearts, in situ, in both failing and nonfailing conditions, has never been done. To address these questions, we will use here novel genetic murine models;; murine models of various types of heart failure;; and investigations with human cells, tissue, and plasma, to investigate in depth the role of BCAAs in heart failure. These highly focused studies will elucidate the role of BCAA catabolism in cardiac function, with a strong focus on human studies.