The PI3K/AKT signaling has crucial role in the regulation of numerous physiological functions through activation of downstream effectors and modulation of cell cycle transition, growth and proliferation. This pathway participates in the pathogenesis of several human disorders such as heart diseases through regulation of size and survival of cardiomyocytes, angiogenic processes as well as inflammatory responses. Moreover, PI3K/AKT pathway participates in the process of myocardial injury induced by a number of substances such as H 2 O 2 , Mercury, lipopolysaccharides, adriamycin, doxorubicin and epirubicin. In this review, we describe the contribution of this pathway in the pathoetiology of myocardial ischemia/reperfusion injury and myocardial infarction, heart failure, cardiac hypertrophy, cardiomyopathy and toxins-induced cardiac injury.