A historical account of the discovery of reversible protein phosphoryltion will be presented. It occurred fifty five years ago during a study undertaken with Ed Krebs to elucidate the complex hormonal regulation of glycogen phosphorylase. While it is extremely simple, it came nevertheless as a complete surprise because essentially nothing was known at that time about the mechanism of enzyme regulation or the structure and function of phosphoproteins. We know today that the process represents one of the most prevalent mechanism by which eukaryotic cellular events are regulated. The study led to the establishment of the first hormonal cascade of enzymes acting on enzymes initiated by cAMP discovered by Earl Sutherland. It also showed how two different physiological processes (carbohydrate metabolism and muscle contraction) could be regulated in concert by the release of calcium ions.