The ability of the heart muscle to derive energy from a wide variety of substrates provides the myocardium with remarkable capacity to adapt to the ever-changing metabolic environment depending on factors including nutritional state and physical activity. There is increasing evidence that loss of metabolic flexibility of the myocardium contributes to cardiac dysfunction in disease conditions such as diabetes, ischemic heart disease and heart failure. At the level of glucose metabolism reduced metabolic adaptation in most cases is characterized by impaired stimulation of transarcolemmal glucose transport in the cardiomyocytes in response to insulin, referred to as insulin resistance, or to other stimuli such as energy deficiency. This review discusses cellular mechanisms involved in the regulation of glucose uptake in cardiomyocytes and their potential implication in impairment of stimulation of glucose transport under disease conditions. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.