Diabetes has been known since antiquity. We present here a historical perspective on the concepts and ideas regarding the physiopathology of the disease, on the progressive focus on the pancreas, in particular on the islets discovered by Langerhans in 1869, leading to the iconic experiment of Minkowski and von Mering in 1889 showing that pancreatectomy in a dog induced polyuria and diabetes mellitus. Subsequently, multiple investigators searched for the active substance of the pancreas and some managed to produce extracts that lowered blood glucose and decreased polyuria in pancreatectomized dogs but were too toxic to be administered to patients. The breakthrough came 100 years ago, when the team of Frederick Banting, Charles Best, and James Collip working in the Department of Physiology headed by John Macleod at the University of Toronto managed to obtain pancreatic extracts that could be used to treat patients and rescue them from the edge of death by starvation, the only treatment then available. This achievement was quickly recognized by the Nobel Prize in Physiology or Medicine to Banting and Macleod in 1923. At 32, Banting remains the youngest awardee of this prize. Here we discuss the work that led to the discovery and its main breakthroughs, the human characters involved in an increasingly dysfunctional relationship, the controversies that followed the Nobel Prize, and the debate as to who actually “discovered” insulin. We also discuss the early commercial development and progress in insulin crystallization in the decade or so following the Nobel Prize.