Cetaceans have evolved many behavioral and biological adaptations to allow them to survive in aquatic environments. Because of diving and breath-holding behaviors, cetaceans experience wide fluctuations in oxygen tension. However, the molecular basis behind their adaptation to a wide range of diving depths and durations remains unknown. Hypoxia-inducible factor (HIF) is a crucial regulator of cellular and systemic responses to low oxygen levels. In this study, the HIF-1 alpha gene was cloned from the sperm whale (Physeter macrocephalus), the beluga whale (Delphinapterus leucas), and the Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis). HIF-1 alpha from the deep-diving sperm whale degraded rapidly under normoxia but remained stable during hypoxia compared with HIF-1 alpha from the beluga whale and the Yangtze finless porpoise. Sperm whale HIF-1 alpha also responded to reoxygenation significantly faster and exerted more potent effects on the transcriptional activity of some gene promoters compared with HIF-1 alpha from the beluga whale and the Yangtze finless porpoise. Mutations in HIF-1 alpha were detected between the Yangtze finless porpoise and the sperm whale, which may determine their functional differences. The results suggest that the response of sperm whale HIF-1 alpha to different oxygen tensions is more variable than that of Yangtze finless porpoise or beluga whale HIF-1 alpha, indicating that the rate of degradation of HIF-1 alpha may be more variable in long-duration divers than in short-duration diver cetaceans. Because of the lack of whale models and whale cell lines, all experiments were conducted in vitro using human embryonic kidney 293T cells.