Aerobic organisms use molecular oxygen (dioxygen; O2) to generate chemical energy in the form of adenine triphosphate (ATP). Energy transforms cellular structure to function, a defining property of life. Due to its favorable thermodynamic properties, O2 appears to have been selected during biological evolution to serve as the terminal electron acceptor in the reduction of carbon-based fuels to generate ATP by oxidative phosphorylation. That O2 is essential to sustain human life is perhaps best illustrated during an acute cardiopulmonary arrest—commonly referred to as ‘‘code blue’’on the medical wards. Indeed, the ‘‘AB-Cs’’of basic life support is to ensure gas-exchange via the lungs and O2 delivery to internal organs:‘‘A’’for airway,‘‘B’’for breathing, and ‘‘C’’for circulation. A less well appreciated role of O2 is in the evolution of organismal size, multicellularity, and biological complexity. An understanding of the key role of O2 in the evolution of complex life and mammalian physiology may provide novel insights of O2, and its metabolites (reactive oxygen species), in the pathophysiology of diseases that affect the lung.