Introduction: Heart failure (HF) has become the cardiovascular epidemic of the century and now imposes an immense burden on health care systems. While our understanding of the pathophysiology of HF has increased dramatically, the translation of knowledge into clinical practice has been disappointing. Metabolic dysfunction in HF has been studied for eight decades, but these efforts have not resulted in effective therapies. This paucity in clinical translation probably results from the variable contribution of metabolic dysfunction to the underlying heart disease. A major unmet need in cardiac drug development is therefore the ability to identify a homogeneous subset of patients in whom HF is driven by a specific mechanism that can be targeted.Areas covered: The available literature was evaluated to describe maladaptive metabolic perturbations that occur in failing hearts and may cause metabolic inflexibility, oxidative stress and cardiac energy depletion. Furthermore, the potential utility of various biomarkers and molecular imaging techniques to detect and quantify specific metabolic dysfunctions in HF were compared. Finally, the authors propose ways to utilize these techniques to select patients for specific metabolic interventions.Expert commentary: Metabolic dysfunction is among the most promising therapeutic targets in HF. Meticulous patient-selection with molecular imaging techniques and specific biomarkers appears indispensable for the effective translation of decades of scientific knowledge into clinical therapeutics.