401 comutase or glucose6-phosphatase, was rate-limiting in the conversion of glycogen to glucose, and that the hormones were acting to increase the activity of this enzyme (3). Glycogen loss was associated not only with an increase in glucose but with increased levels of both glucose 1-phosphate and glucose 6-phosphate. An important problem complicating analysis at this stage was the accepted theory or assumption that phosphorylase catalyzed the in vivo synthesis of glycogen as well as its degradation. We knew that the hormones always stimulated glycogen breakdown rather than synthesis so that, even after phosphorylase activation had been demonstrated in response to the hormones (Fig. 1), an additional factor was suspected. One factor preventing phosphorylase from catalyzing glycogen synthesis in vivo was the high ratio of inorganic phosphate to hexose phosphate, which normally prevails inside cells. Glycogen synthetase was not discovered until later (5), and we now know that its activity is decreased while phosphorylase activity is increased (6) as a result of the same basic reaction