With the global prevalence of heart disease continuing to increase and large populations living at altitude around the world, we review the concept of altitude and cardioprotection. Current epidemiologic data, as well as the basic science and molecular mechanisms involved in acute, intermittent, and chronic exposure to altitude, are discussed. Intermittent and chronic exposures have been demonstrated to increase coronary vasculature, decrease infarction size, and provide more efficient metabolism and better cardiac functional recovery postischemia. Mechanisms demonstrated in these situations include those mediated by the hypoxia inducible factor, as well as reactive oxygen species, certain ion channels, and protein kinases. Although current epidemiologic studies are difficult to interpret owing to many confounders, many studies point to the possibility that living at altitude provides cardiovascular protection. Further research is needed to determine if the bench studies showing mechanisms consistent with cardioprotection translate to the population living at altitude.