Connexin 43 (Cx43) is the constitutive protein for the formation of cardiac gap junctions and therefore essential for cell-cell coupling and normal cardiac function. Apart from its localization at the sarcolemma, Cx43 is present in the inner mitochondrial membrane. Cx43 is involved in cardiomyocyte free oxygen radical formation and in the cardioprotection by ischemic preconditioning (IP). This review will discuss Cx43 deficiency in aged and diseased myocardium and the potential impact of age and disease on IP's cardioprotection.