Cardiac NCX is modulated by diverse regulatory elements. Although there is consensus about the regulatory function of Na+ and Ca2+ and other elements, for example, ATP, there is still a controversial debate about the functional role of cyclic nucleotides and protein kinases. Future studies should focus on that topic since disturbances of cAMP/cGMP concentration and kinase activity may lead to severe functional disorders in the diseased heart. S100A1 is presumably a novel regulator of NCX.