A historical account of the discovery of reversible protein phosphorylation will bepresented. It occurred about 60 years ago during a study undertaken with Ed Krebs toelucidate the complex hormonal regulation of glycogen phosphorylase. It was shown that the reaction was triggered by Ca2+, Mg 2+ and ATP. It led to the establishment of the first hormonal cascade of enzymes acting successively on one another, initiated by cAMP and discovered by Earl Sutherland. We know today that the process represents one of the most prevalent mechanism by which eukaryotic cellular events are regulated, being involved in the control of many physiological processes as well as hereditary, bacterialand viral diseases. Most forms of cancer result from an imbalance of this system. It also showed how two different physiological processes (carbohydrate metabolism and muscle contraction) could be regulated by the release of calcium ions. A couple of video clips of Ed Krebs speaking of our early work will be shown.