Tissue hypoxia and ischemia–reperfusion pose a dangerous situation for oxidative stress. However, diving mammals and birds show pronounced resistance to oxidative injury under such conditions, which are a consequence of selective vasoconstriction during a dive. As the function of Hypoxia-Inducible Factor-1α (HIF-1α) in protection against and adaptation to hypoxia has been recognized in terrestrial animals, we have investigated the genomics and expression of this protein in ringed seal (Phoca hispida) in order to determine if it may play a protective role in this diving mammal. PCR studies using primers based on sequences from mouse HIF-1α exons 3, 4, 5, 6, 9, 10, 11, 12 and 15 showed that DNA from seal lung generated PCR products similar to those from mouse DNA. These studies have established that a putative HIF-1α gene exists in the seal genome that appears to have a similar but not identical sequence to the mouse gene. Seal lung and skeletal muscle tissues showed the highest relative levels of HIF-1α protein expression, with heart muscle showing significantly lower levels, and levels of HIF-1β protein expression paralleled this situation. Analysis of oxidized cellular protein levels indicated that seal lung and heart muscle had the lowest levels of oxidized proteins. Thus, as seal lung tissue had the highest level of HIF-1α protein expression and the second lowest level of protein oxidation, this suggests that HIF-1α expression may have an important protective effect in this tissue in diving mammals. Our results support the hypothesis that HIF-1α expression is dependent on both tissue-specific energy requirements and adequate metabolic supply-to-demand ratio. Combined, the evidence available suggests that diving mammals have an overall anticipatory response to avoid the ill effects of dive-associated ischemia–reperfusion which may involve the HIF-1 system.