The broad definition of "conditioning" is the application of a series of alternating intervals of brief ischemia (hypoxia) and reperfusion (reoxygenation) applied in the setting of prolonged ischemia causing myocardial infarction. While the conditioning stimulus is applied before the major (index) ischemic event in ischemic preconditioning, it is applied during the event in perconditioning, and applied after the event (reperfusion) in postconditioning. Studies on perconditioning have only recently demonstrated a reduction in infarct size by remote ischemia applied during transport of heart attack victims to the hospital before percutaneous coronary interventions (PCIs). The "conditioning" paradigm has been extended to include remote perconditioning and remote postconditioning. However, the biology of perconditioning is virtually unknown. Postconditioning has enjoyed enthusiastic attention from scientists that have done much to demonstrate that the model of triggers, mediators, and effectors used in preconditioning may also apply to postconditioning, with the addition and important contribution of physiological mechanisms resulting in cardioprotection, including gradual normalization of tissue pH, reduction in generation of reactive oxygen species, and avoidance of hypercontracture. This same schema has not been confirmed in perconditioning. However, the unknowns in both conditioning paradigms far outweigh the knowns. Why postconditioning does not exert cardioprotection in experimental models of comorbidities and aging, yet reduces postischemic injury and contractile dysfunction in older patients with multiple comorbidities is a conundrum for which no answers are forthcoming. The optimal algorithm is unknown, as is the interrelationship between the many molecular, cellular, and physiological pathways that purportedly "mediate" or "trigger" the conditioning responses. Whether there are common pathways engaged in all 3 forms of conditioning, and what nuances separate one form of conditioning from another are unanswered questions. Yet, the translational potential of per- and postconditioning will drive further experimental work and clinical trials, which will ask unprecedented cooperation and information sharing between basic and clinician scientists, and creative developments from industry.