The S100 protein family is the largest group of EF-hand signaling proteins in humans. The members of the S100 protein family are expressed in many tissues and play different functions. Many diseases are related to S100 proteins, which function as new biochemical markers especially in cardiac diseases. The most studied members, protein S100B and protein S100A1, exhibit activities in cardiac diseases, and these immunohistochemical expressions or serum levels have been used in predicting neurologic outcome after resuscitation of cardiac arrest or recovery of cardioprotective function.