Although the pathogenesis of the diabetes mellitus syndrome remains poorly understood, both insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus predispose the individual to a similar spectrum of complications, including hypertension, macrovascular and microvascular disease, cataracts cardiomyopathy, neuropathy, and premature aging, suggesting that these complications develop along a pathway common to both diabetic conditions. Yet not all diabetic persons are affected by all of these complications or to the same degree. What causes this marked variability in the clinical manifestations of the diabetes syndrome remains an enigma. Accumulating data from animal models of diabetes and from studying patients with diabetes reveal that intracellular calcium levels are increased in most tissues. The activities of the membrane, adenosine triphosphatase (ATPase) associated cation pumps, which determine intracellular calcium level (i.e., calcium-ATPase and [sodium + potassium]-ATPase), are also altered. The nature of the alteration is often tissue specific and may depend on the level of blood glucose or insulin, or both. In this review we discuss the potential contribution of these changes in intracellular calcium regulation, whether acquired or genetically determined, to the pathogenesis of the diabetes syndrome, to the abnormalities in insulin secretion and action (mainly in non-insulin-dependent diabetes), and to the complications of both diabetes syndromes. Altered intracellular calcium metabolism may represent a common, underlying abnormality linking the metabolic, cardiovascular, ocular, and neural manifestations of the diabetic disease process.