Myocardial ischemia induces cardiomyocyte injury and death, resulting in impairment of cardiac function. As the endogenous protective function of adult cardiomyocytes is limited, nonmyocytic cells can be activated to protect myocardium from ischemic injury. In this article, we summarize nonmyocytic mechanisms involved in myocardial protection against ischemic injury. In particular, we review a novel concept of cardioprotection: upregulation of genes encoding liver cell-secreted factors in response to experimental myocardial ischemia and alleviation of acute myocardial infarction by administration of myocardial ischemia-conditioned liver cell extract. We present experimental evidence that supports this concept.