In the Western world, cardiac ischemic disease is still the most common cause of death despite significant improvements of therapeutic drugs and interventions. The fact that the heart possesses an intrinsic protection mechanism has been systematically overlooked before the 1980s. It has been clearly shown that the activation of this mechanism can reduce the infarct size after an ischemic insult. Prerequisite is the induction of the synthesis of such cardio-protective proteins as heat shock proteins (HSPs) and anti-oxidative enzymes. HSPs are involved in the maintenance of cell homeostasis by guiding the synthesis, folding and degradation of proteins. Besides, the various family members cover a broad spectrum of anti-oxidative, anti-apoptotic and anti-inflammatory activities. Although the major inducible HSP72 has received most attention, other HSPs are able to confer cardioprotection as well. In addition, it seems that there is a concerted action between the various cardio-protective proteins. One drawback is that the beneficial effects of HSPs seem to be less effective in the compromised than in the normal heart. Although clinical studies have shown that there is a therapeutic potential for HSPs in the compromised heart, major efforts are needed to fully understand the role of HSPs in these hearts and to find a safe and convenient way to activate these protective proteins.