Ischemia and reperfusion injury is a dynamic process that involves multiple organ systems in various clinical states including transplantation, trauma, and surgery. Research into this field has identified key molecular and signaling players that mediate, modulate, or augment cellular, tissue, and organ injury during this disease process. Further elucidation of the molecular mechanisms should provide the rationale to identify much-needed novel therapeutic options to prevent or ameliorate organ damage due to ischemia and reperfusion in clinics.