The blind subterranean mole rat of the Spalax ehrenbergi superspecies, living underground and exposed to fluctuating oxygen and carbon dioxide levels, is an excellent model of hypoxic tolerance. Unique structural and functional adaptations of the cardiovascular and respiratory systems allow these underground mammals to survive at severely reduced oxygen tension. Elucidation of the natural variation and evolutionary changes under hypoxia within this superspecies may have biomedical applications in ischemic syndromes and cancer. In this study, we have compared expression profiles of muscle tissue at normoxic (21%) and hypoxic (3%) levels of oxygen concentration between two allospecies of the S. ehrenbergi superspecies exhibiting differential hypoxia tolerance in accordance with their ecological regimes. Profiling was performed by cross-species hybridization using a mouse cDNA array containing 15,000 gene elements. Results uncover species-specific responses to hypoxic stress among numerous genes involved in angiogenesis, apoptosis, and oxidative stress management. Among the most striking results are differential expressions of cardiac ankyrin repeat protein ( Carp), activating transcription factor 3 ( Atf3), LIM and cysteine-rich domains 1 ( Lmcd1), cysteine and glycine-rich protein 2 ( Csrp2), and ras homolog gene family, member B ( RhoB). These findings support the hypothesis that allospecies of the S. ehrenbergi superspecies are variably adapted to fluctuating oxygen tension. Differences may involve specific metabolic pathways and functional adaptations at the structural and molecular levels.