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Hypoxia-inducible factors (HIF) are components of an endogenous oxygen-sensing system. HIF-1α is stimulated by hypoxia, as occurs in ischemia. A transcriptional activation of gene and protein expression provides cellular protection against many types of stress. HIF prolyl 4-hydroxylase (PHD) enzymes are responsible for HIF oxygen sensing and increased cellular protective transcription changes. Under normoxia, hydroxylation of HIF-1α by PHD results in endogenous HIF degradation and thus suppression of the HIF signaling pathway. Under hypoxia or in the presence of PHD inhibition, hydroxylation of HIF-1α by PHD cannot occur. As a result, HIF-1α is not degraded but instead dimerizes with HIF-1β, resulting in the stimulation of protective gene and protein expression. Thus, a short period of ischemia to a tissue bed (eg, as used in ischemic preconditioning paradigms) and inhibition of PHD can both result in tissue or end-organ protection. In this paper, we discuss the regulation of oxygen sensing by PHD and the effects of PHD inhibition on cellular protection via HIF.