Activation of endogenous signal transduction pathways, by a variety of stimuli including ischemic and anesthetic pre- and post-conditioning, protects myocardium against ischemia and reperfusion injury. Experimental evidence suggests that adenosine-regulated potassium channels, cyclooxygenase-2, intracellular kinases, endothelial nitric oxide synthase, and membrane bound receptors play critical roles in signal transduction, and that intracellular signaling pathways ultimately converge on mitochondria to produce cardioprotection. Disease states, and perioperative medications such as sulfonylureas and COX-2 antagonists, could have adverse effects on cardioprotection by impairing activation of ion channels and proteins that are important in cell signaling. Insights gained from animal and clinical studies are reviewed and recommendations given for the use of perioperative anesthetics and medications.