An intriguing relationship between IGF-I action and cardiac function has been noted for some time, but exactly how IGF-I modulates myocardial function remained obscure. Recent research shed novel insight into potential mechanisms of IGF-I actions in cardiac muscle. New discoveries help elucidate the role of IGF-I signaling in protecting cardiac muscle against injuries, and support potential therapeutic roles for IGF-I in cardiomyopathy. Multiple actions of IGF-I has been described in cardiac muscle cells, including the well-documented anti-apoptosis effect and the newly emerged action on cardiac muscle regeneration. Furthermore, interplay between heat shock protein and IGF-I receptor signaling has been identified and this new paradigm might be involved in the development of diabetic cardiomyopathy. This article reviews recent research findings and outlines potential therapeutic implications of IGF-I in heart failure.