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The discovery of insulin in 1921 - due to the efforts of the Canadian research team based in Toronto - has been a landmark achievement in the history of medicine. Lives of people with diabetes were changed forever, considering that in the pre-insulin era this was a deadly condition. Insulin, right after its discovery, became the first hormone to be purified for human use, the first to be unraveled in its amino acid sequence and to be synthetized by DNA-recombinant technique, the first to be modified in its amino acid sequence to modify its duration of action. As such the discovery of insulin represents a pivotal point in medical history. Since the early days of its production, insulin has been improved in its pharmacokinetic and pharmacodynamic properties in the attempt to faithfully reproduce diurnal physiologic plasma insulin fluctuations. The evolution of insulin molecule has been paralleled by evolution in the way the hormone is administered. Once-weekly insulins will be available soon, and glucose-responsive "smart" insulins start showing their potential in early clinical studies. The first century of insulin as therapy was marked by relentless search for better formulations, a search that has not stopped yet. New technologies may have, indeed, the potential to provide further improvement of safety and efficacy of insulin therapy and, therefore, contribute to improvement of the quality of life of people with diabetes., Competing Interests: Declaration of competing interest SDP has received lecture and/or advisory fees from Applied Therapeutics, Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Sanofi, Takeda Pharmaceuticals. He also receives research support from AstraZeneca and Boehringer Ingelheim. PF, MA, AB, CB, FC and MG have no potential conflicts to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)