The prevalence of the cardiovascular disease significantly affects the outcome of both cardiac and non-cardiac surgery, and perioperative cardiac morbidity is one of the leading causes of death following anesthesia and surgery. The considerable incidence of myocardial infarction, congestive heart failure, myocardial ischemia, or serious dysrhythmias during the intraoperative or postoperative periods, has led many studies to examine medical factors and interventions for decreasing cardiac risk in patients with cardiovascular disease. An extensive amount of work has focused on whether any one anesthetic agent or technique is particularly beneficial for patients with coronary artery disease. Experimental studies conducted in our laboratory have clearly shown that volatile anesthetics may exert profound cardioprotection against myocardial ischemia and reperfusion injury. This article examines the recent evidence about the importance of mitochondria, reactive oxygen species and the KATP channels in cardioprotective signaling by volatile anesthetics. Moreover, the article addresses current concepts and controversies regarding specific roles of the mitochondrial and the sarcolemmal KATP channels in anesthetic-induced preconditioning.