This study reviews the current understanding of ischemic preconditioning (IP) in experimental and clinical setting, and the mechanisms that mediate the complex processes involved as a tool to protect against ischemia and reperfusion (I/R) injury, but is not intended as a complete literature review of preconditioning. IP has been mainly elucidated in cardiac ischemia. Recent reports confirm the efficacy of pre- and postconditioning in cardiac surgery and percutaneous coronary interventions in humans. IP utilizes endogenous as well as distant mechanisms in skeletal muscle, liver, lung, kidney, intestine and brain in animal models to convey varying degrees of protection from I/R injury. Specifically, preconditioned tissues exhibit altered energy metabolism, better electrolyte homeostasis and genetic reorganization, as well as less oxygen-free radicals and activated neutrophils release, reduced apoptosis and better microcirculatory perfusion. To date, there are few human studies, but recent trials suggest that human liver, lung and skeletal muscle acquire protection after IP. Present data address the potential therapeutic application of IP in the prevention of I/R damage specially aimed at clinical transplantation. IP is ubiquitous but more research is required to fully translate these findings to the clinical arena.