Conditioning refers to endogenous mechanisms rendering the myocardium more tolerant against reperfusion injury. Application of brief ischemia-reperfusion cycles prior to the index ischemia has a beneficial effect and limits the infarct size. This is called preconditioning and is mainly mediated by activation of adenosine, bradykinin, opioid and other receptors, with subsequent activation of intracellular mediators leading to mitochondrial protection. A clinical equivalent of preconditioning is preinfarction angina. Benefits for the ischemic and reperfused myocardium are also provided by repetitive short-lived cycles of ischemia-reperfusion applied after the index ischemia. This is termed postconditioning, shares a common pathway with preconditioning, and is more useful and relevant in clinical practice. Finally, benefits are also derived from remote conditioning, i.e. ischemia applied in a remote vascular territory parallel with or immediately after the index myocardial ischemia. Several pharmacological interventions may interfere with these mechanisms leading to enhanced protection of the myocardium and limitation of the infarct size. Despite the huge interest and the great body of evidence that verify the effectiveness of conditioning, clinical application has remained limited due to controversies over the appropriate intervention protocol, but also interference of medication, comorbidities and other factors that may enhance or blur the protective effect.