1. The mechanism of hormonal action remained a complete mystery for almost 50 years, because effects always disappeared when the target tissue was homogenized. In the early 1950s, Earl Sutherland reproduced the effect of a hormone in a cell homogenate for the first time (the stimulation of hepatic glycogenolysis by adrenaline) and showed that adrenaline exerted its effect by inducing the production of a dialyzable heat-stable factor.[1] How the factor was identified a few years later as adenosine 3', 5'-cyclic monophosphate (cyclic AMP) is beautifully described in the book, Cyclic AMP, by G.A. Robison, R.W. Butcher, and Earl Sutherland (Academic Press, 1970). I regard the discovery of cyclic AMP, the first "second messenger," as one of the greatest biological discoveries of the 20th Century. Earl Sutherland was so far ahead of his time that his work was regarded with disbelief for a number of years.