Some mammals respond to hypoxia by lowering metabolic demand for oxygen and others by maximizing efficiency of oxygen usage: the former strategy is generally held to be the more effective. We describe within the same species one outbred strain (CD1) that lowers demand and another inbred strain (C57BL6J) that maximizes oxygen efficiency to markedly extend hypoxic tolerance. Unanesthetized adult male mice (Mus musculus, CD-1 and C57BL6J) between 20-35 grams were used. Sham Conditioned (SC) C57BL6J mice survived severe hypoxia (4.5% O₂ balanced N₂) roughly twice as long as SC CD-1 mice (median 211 s, 93.5 s respectively; p<0.0001). Following acute hypoxic conditioning (HC), C57BL6J mice survived subsequent hypoxia 10 times longer than HC CD-1 mice (median 2,198 s, 238 s respectively; p<0.0001). Therefore, C57BL6J mice are both naturally more tolerant to hypoxia and show a greater increase in hypoxic tolerance in response to hypoxic conditioning. Indirect calorimetry indicates that CD-1 mice lower mass-specific oxygen consumption (V' O₂ in mL O₂*Kg^-1*min^-1) and carbon dioxide production (V' O₂ in mL CO₂*Kg^-1*min^-1) in response to HC (p=0.002 and p<0.0001 respectively), but, C57BL6J mice maintain V' O₂ and V' O₂after HC. Respiratory Exchange Ratio (RER) and fluorometric assay of plasma ketones suggest that C57BL6J mice rapidly switch to ketone metabolism, a more efficient substrate, while, CD-1 mice reduce overall metabolic activity. We conclude that under severe hypoxia in mice, switching fuel, possibly to ketones, and while maintaining V' O₂ may confer a greater survival advantage than simply lowering demand.