Organ preservation and reperfusion injury have significant detrimental effects on both short- and long-term organ function. Ischemia reperfusion injury (IRI) underlies organ transplant dysfunction, myocardial infarction, stroke, and shock. Multiple molecular pathways are engaged in reactive oxygen production, apoptosis, signaling, and tissue regeneration. There has been an increased understanding of the important role of immune and inflammatory pathways in IRI, both in humans and in experimental models. Both cellular and soluble components of the immune system are directly activated during IRI, and there is evidence that immune mediators directly contribute to organ dysfunction. Immune activation during IRI likely underlies the enhanced immunogenicity of ischemic organs, with resultant increased rejection and fibrosis. Novel human therapies targeting T and B cells for classic immune diseases can now be considered to prevent and treat IRI. Organ preservation injury and cold ischemia could well have distinct pathophysiology from warm IRI and represent an opportunity to develop improved preservation methods.