Cardiac disease is commonly associated with changes in energy substrate metabolism. Fatty acid and glucose represent the main fuels used by the heart, and characteristic alterations in substrate preference and utilisation occur early in many cardiac disease processes. Different substrate classes (lipids, carbohydrates) have different metabolic efficiencies, both in terms of energy (ATP) yield and in terms of oxygen requirement; changes in metabolic efficiency may affect, positively and negatively, cardiac function. Furthermore, metabolic diseases alter substrate supply to the heart, which may have an impact on cardiac function. One challenge is to establish whether a primary metabolic abnormality in myocardial fuel utilisation leads to cardiac dysfunction, or whether changes in substrate selection are a consequence of the disease state. The distinction is important as the ability to manipulate cardiac substrate utilisation may offer a therapeutic opportunity for cardiac disease.