Preconditioning, which was first described in 1986, demonstrates that preservation of ischemic myocardium is at least theoretically possible. An appreciation of the putative biochemical pathway of preconditioning would allow the clinician to precondition the heart pharmacologically. During ischemia, numerous agents are released by the myocardium, including adenosine, catecholamines, angiotensin II, bradykinin, and endothelin. All of these agents can contribute to preconditioning, but adenosine, acting through its A1 receptor, is central to the preconditioning phenomenon. Current evidence suggests that adenosine and its receptor elicit protection through the activation of protein kinase C (PKC). Many agonists of PKC-coupled receptors are released by the ischemic myocardium, and exogenous administration of any one of these is capable of eliciting protection. The ATP-sensitive potassium (K+ ATP) channel remains the most likely candidate for the ultimate preconditioning end-effector. Human hearts can be preconditioned, and angioplasty has emerged as a powerful tool for testing preconditioningmimetic agents in man. Preconditioning’s early protective phase is followed by a delayed phase of protection, the “second window of protection,” which might be more amenable to prophylactic treatment of high-risk patients. As our knowledge of preconditioning’s mechanism grows, more and more strategies for protecting the ischemic myocardium are sure to emerge...