The reduction or cessation of the blood supply to an organ results in tissue ischemia. Ischemia can cause significant tissue damage, and is observed as a result of a thrombosis, as part of a disease process, and during surgery. However, the restoration of the blood supply often causes more damage to the tissue than the ischemic episode itself. Research is therefore focused on identifying the cellular pathways involved in the protection of organs from the damage incurred by this process of ischemia reperfusion (I/R). The hypoxia-inducible factors (HIFs) are a family of heterodimeric transcription factors that are stabilized during ischemia. The genes that are expressed downstream of HIF activity enhance oxygen-independent ATP generation, cell survival, and angiogenesis, amongst other phenotypes. They are, therefore, important factors in the protection of tissues from I/R injury. Interestingly, a number of the mechanisms already known to induce organ protection against I/R injury, including preconditioning, postconditioning, and activation of signaling pathways such as adenosine receptor signaling, converge on the HIF system. This review describes the evidence for HIFs playing a role in I/R protection mediated by these factors, highlights areas that require further study, and discuss whether HIFs themselves are good therapeutic targets for protecting tissues from I/R injury.