If evolution is an accurate statement of our biology, then disease must be tightly associated with its patterns. We considered selection for more optimal capacity for energy transfer as the most general pattern of evolution. From this, we propose that the etiology of complex disease is linked tightly to the evolutionary transition to cellular complexity that was afforded by the steep thermodynamic gradient of an oxygen atmosphere. In accord with this thesis, clinical studies reveal a strong statistical link between low aerobic capacity and all-cause mortality. In addition, large-scale unbiased network analyses demonstrate the pivotal role of oxygen metabolism in cellular function. The demonstration that multiple disease risks segregated during two-way artificial selection for low and high aerobic capacity in rats provides a remote test of these possible connections between evolution, oxygen metabolism, and complex disease. Even more broadly, an atmosphere with oxygen may be uniquely essential for development of complex life anywhere because oxygen is stable as a diatomic gas, is easily transported, and has a high electronegativity for participation in energy transfer via redox reactions.