Diabetic cardiomyopathy is a distinct entity in humans. It leads to ventricular dysfunction independent of and additive to coronary artery disease and hypertension. Clinical and experimental studies have pointed to the role of metabolic derangements in the development of diabetic cardiomyopathy. Altered insulin signaling in diabetes leads to decreased myocyte glucose uptake and utilization, associated with an increased concentration of free fatty acids. This results in decreased glucose oxidation and increased fatty acid oxidation. Fatty acids increase mitochondrial oxygen consumption for ATP production and stimulate the uncoupling proteins in mitochondria. These proteins decrease the mitochondrial protein gradient, leading to fall in ATP production. The resultant defect in myocardial energy production impairs myocyte contraction and diastolic function. This is the hallmark of diabetic cardiomyopathy at earlier stages. In later stages diabetes impairs the myocyte ischemic defense mechanism, leading to increased cardiovascular morbidity and mortality. Other factors contributing toward causation of diabetic cardiomyopathy are collagen accumulation leading to reduced myocardial compliance, accumulation of advanced glycation end product-modified extracellular matrix proteins with subsequent inelasticity of vessel walls and myocytes, abnormal myocardial calcium handling leading to altered mechanics, endothelial dysfunction, cardiac autonomic neuropathy, and impairment of ischemic preconditioning. Trimetazidine acts a metabolic switch, favoring glucose over free fatty acids as the substrate for metabolism in cardiac myocytes.