S100A1, a small EF-hand Ca(2+)-binding protein with intracellular and extracellular functions, is predominantly expressed in cardiac muscle where it plays a crucial role as a modulator of Ca(2+) homeostasis, energy metabolism and contractile performance. Essentially, its beneficial effects on heart function have been attributed to its direct interaction with, and effects on, sarcoplasmic reticulum calcium handling proteins sarco(endo) plasmic reticulum Ca(2+) ATPase and the ryanodine receptor. Downregulated levels of S100A1 in cardiomyocytes postmyocardial infarction have been linked to diminished cardiac reserve and contribute to the development of heart failure. Interestingly, S100A1 expression has recently been described in endothelial cells where it is downregulated in heart failure and has been shown to modulate intracellular Ca(2+) levels and nitric oxide production. Absence of the Ca(2+) sensor protein in endothelial cells is associated with endothelial dysfunction and hypertension. Thus, S100A1 is emerging as a potential therapeutic target for diverse cardiovascular conditions.