Cytochrome c oxidase (CcO, complex IV) is the last component of the respiratory chain, catalyzing the reduction of oxygen to water and the translocation of protons to the inner membrane space. In 1925, David Keilin published his work on the rediscovery of cytochromes, including types a and a<inf>3</inf>. The same year, Otto Warburg published part of his work on the “respiratory ferment”. Both articles are fundamental to bioenergetics and the mitochondrial field. Since its discovery, CcO has been the subject of study in hundreds of laboratories across the world, but there are still many interrogates to be answered. To commemorate the 100^th anniversary of the publication of these two seminal works, this review examines various aspects of the history of CcO (complex IV) and the challenges yet to be resolved of this enzyme.