Myocardial ischemia and reperfusion (I/R) is a common problem in clinic and there is no satisfactory method for prevention or treatment of I/R injury so far. Chronic intermittent hypobaric hypoxia (CIHH), similar to the concept of ischemia preconditioning (IPC)or altitude hypoxia adaptation (AHA), has been recognized to confer a protective effect on heart against I/R injury with a longer protective effect than IPC and a less adverse effect than AHA. It has been proved that CIHH increases myocardial tolerance to ischemia or hypoxia, reserving cardiac function and preventing arrhythmia during I/R. Multiple mechanisms or pathway underlying the cardiac protection of CIHH have been proposed, such as induction of heat-shock protein, enhancement of myocardial antioxidation capacity, increase of coronary flow and myocardial capillary angiogenesis, activation of adenosine triphosphate (ATP)-sensitive potassium channels, inhibition of mitochondrial permeability transition pores, and activation of protein kinase C (PKC) and induced nitric oxide synthase (iNOS). In addition, CIHH has been found having many beneficial effects on the body, such as promotion of health, increase of oxygen utilization, and prevention or treatment for some diseases. The beneficial effects of CIHH and potential mechanisms are reviewed mainly based on the researches performed by our group.