Force generation in the heart is ultimately a cellular event. Hence, any alteration in the pumping ability of the heart must reflect a change in some aspect of the process of excitation-contraction or relaxation at the cellular level. Much data have supported a close, direct association of the changes in cell Ca2+ concentrations with the contractile event in the heart. Calcium entry from the extracellular space into the myocardial cell during the action potential elicits contraction. Free Ca2+ concentrations in the cytoplasm will rise to 10−5 M during tension generation and then return to 10−7 M upon relaxation of the cell. Obviously, therefore, the factors which regulate Ca2+ homeostasis in the cell and those compounds in the cell which interact with Ca2+ ions are of paramount importance to the contractile status of the heart. Several structures in the myocardial cell are ultimately involved in the control of tension generation and relaxation in the heart. The sarcolemmal membrane, the sarcoplasmic reticulum (SR), the mitochondria, and the contractile proteins are the principal subcellular organelles involved in contraction-relaxation in the normally functioning heart. Since these organelles are important for the viability and function of the normal healthy myocardium, it is reasonable to postulate that a lesion in these organelles may be associated with the functional depression observed in many disease conditions. The likelihood of such hypothesis being correct has prompted much experimental investigation. The possibility that the functional abnormalities associated with diabetes mellitus may result from significant defects in the viability of various organelles has been addressed by a number of independent laboratories in several countries. Lesions in various subcellular organelles have been identified and extensive investigation has characterized the nature of such lesions. In the subsequent sections, the present state of our knowledge concerning the functional integrity of the contractile proteins, sarcolemma, mitochondria, and SR in cardiac tissue from diabetic animals is discussed. How these defects may relate to the observed depression in force generation in the diabetic heart will also be addressed.