Sometimes “failed” experiments lead to surprising results which turn out to be of higher importance than their expected outcomes. Henry Dale's powers of observation and his scientific instinct to draw the right conclusions from űnsuccessfully conducted” tests, are paragons of the innovational strength of serendipity. When he reversed the known blood pressure-increasing activity of adrenaline by the administration of ergot alkaloids, he explained the observed effect by the existence of two disparate activities of the hormone. His postulation of two types of “receptive substances” located in the arterioles was only confirmed by the discovery of the α- und β- adrenoreceptors forty years later. By the administration of an ergot extract, and the thereby induced reduction in heart rate, he observed the activity of acetylcholine, which his project team isolated from a biological source the very first time. The German-US-American pharmacologist Otto Löwi, Henry Dale, and Wilhelm Feldberg corresponded the identity of acetylcholine with the unknown “vagus substance” which Löwi had discovered in his historical frog heart experiment proving the transduction of nerve impulses through chemical signals. On the other hand, Dale and Burroughs, Wellcome & Co. were dealt a bitter setback as the uterotonic ergotoxin could not fulfill the expectations of the British physicians. Not until 1918, did the Swiss natural product chemist Arthur Stoll accomplish the isolation of the first pure ergot alkaloid, the ergotamine. This metabolite was approved for treatment in gynecology, obstetrics, and acute migraine attacks. In 1922, Henry Dale could no longer rule out that other substances, beyond ergotoxin and ergotamine, may be the real uterotonic and vaso-constrictive agents in ergot. His suspicions were validated when, in 1932, the young Scottish gynecologist Chassar Moir demonstrated the uterotonic activity of a previously undiscovered molecule. © 2023, John Wiley and Sons Inc. All rights reserved.