Since cyanobacteria began to photosynthesize and introduce the colorless and odorless gas oxygen into the earth's atmosphere some 2.5 billion years ago, human evolution has been intrinsically linked to this critical molecule. Initially, the electrophilic chemical properties of oxygen rendered it a formidable toxic challenge to organisms; however, eukaryotic cells, following the incorporation of bacterial-derived mitochondria, evolved to make beneficial use of the chemical properties of molecular oxygen as the final electron acceptor in the highly efficient production of cellular energy supplies in the form of adenosine triphosphate. Because of both its necessity for eukaryotic life and its reactive chemical nature, however, a delicate balance exists between the supply of oxygen to a cell/tissue/organism and the beneficial or harmful outcome. In this minireview, we shall discuss the role of oxygen in metabolism with a particular emphasis on outcomes when oxygen supply is significantly altered. Furthermore, we will describe endogenous mechanisms that have evolved to protect cells and tissues during such adverse conditions and may prove useful as novel therapeutic targets in a range of disease states where oxygen-related stress occurs.