Myocardial adaptation to ischemia in the form of ischemic preconditioning is clinically attractive, but not directly usable until molecular mimics are discovered. A growing body of evidence indicates that events underlying myocardial adaptation to ischemia may either involve, or be parallel to, signaling of the innate immune response. Preconditioning-like protection of the heart can be evoked through giving cytokines or fragments of bacterial walls. A possible role for cytokines, toll-like receptors, and nuclear factor kappa B for evoking ischemic preconditioning are discussed. Through stimulating innate immunity, there is potential to bring preconditioning into the clinics in a reasonable time frame. The possibility that the underlying protective response may involve adaptive immunity through danger signaling is briefly reviewed.