In Plastic and Reconstructive Surgery, ischemia reperfusion injury (IRI) prevention is of utmost importance in free flaps and vascularized composite allotransplantation (VCA) to continue increasing accessibility to these advanced reconstructive options. At present, free flaps and VCA undergo irreversible ischemic damage at 3 hours due to the highly metabolic nature of skeletal muscle, and static cold storage (SCS) can only extend this to 4–6 hours. It is important to understand that one of the major challenges with transplanting composite tissues is that each tissue has a unique tolerance and mechanism to ischemia-reperfusion. Research targeting attenuation of IRI can be subdivided into 3 time periods: the pre-ischemic, ischemic, and post-ischemic. In the pre-ischemic period, there are conditioning methods, the delay phenomenon, which is already used clinically, pharmacologic, and stem cell strategies. In the ischemic period, SCS is used clinically, whilst other preservation methods including cryopreservation, vitrification, machine perfusion, and pharmacologic strategies are being studied. Lastly, in the post-ischemic period, our greatest clinical tool is close post-operative monitoring, however conditioning methods, and pharmacologic strategies have been studied. This chapter covers IRI in tissues implicated in free flaps and VCA, and several prevention strategies either currently in use or in pre-clinical studies.