During the past two decades (i.e., since 1980), in excess of 1000 published papers have focused on the phenomenon of the 'stunned myocardium', with many of these studies seeking to identify mechanisms-based treatment strategies to attenuate post-ischemic contractile dysfunction. Early investigations focused largely on abrogating the deleterious effects of oxygen-derived free radicals and unfavorable alterations in calcium homeostasis, both considered to contribute significantly to the pathogenesis of the stunned myocardium. More recently, favorable results have also been obtained using a somewhat different paradigm: that is, attempting to capitalize on endogenous cardioprotective mediators, most notably adenosine, nitric oxide, and the ATP-sensitive potassium channel. Now that potential therapeutic candidates have been identified in the experimental laboratory, the as-yet unmet challenge is to translate this information into the design of effective pharmacologic therapies to treat myocardial stunning in the clinical arena.