Effective cardioprotection in clinical settings requires not only cardiomyocyte survival but also preservation of fonction. Multiple growth factors protect the heart from ischemic and other injury. While the downstream signaling pathways of these cardioprotective factors are complex, activation of phosphoinositide 3–kinase (PI 3–kinase) and its downstream effector, the serine-threonine kinase Akt (or Protein Kinase B), is a common feature in many cases. Genetic manipulations in cardiomyocytes both in vitro and in vivo suggest that acute activation of this pathway can promote both cardiomyocyte survival and function. Here, we review PI 3–kinase and Akt signaling, with a focus on their role in cardiomyocyte growth, survival, and function. Finally, the clinical implications of these studies will be considered.