Since the findings of Murry and Currie et al. that ischemic preconditioning (IPC) and heat shock response (HSR) could protect evidently myocardium against ischemia-reperfusion injury in the middle of 1980s, endogenous myocardial protection has drawn widespread attentions. A great quantity of studies completed during the past 25 years made much progress in endogenous myocardial protection. Abundant research experiences have been accumulated and a basic theoretical framework has been established in this field. However, there are still many questions need to be solved. In this review, we focused on clarifying some hot questions and important future directions in IPC, heat shock proteins (HSPs), research models and strategies in endogenous myocardial protection.