This article highlights selected milestones in insulin discovery and its continued development as a pivotal therapy for diabetes. The last 90 years have witnessed tremendous progress in insulin therapy, from the initial crude, yet life-saving, animal insulin extracts to novel human insulin analogues. Although the complete physiologic replacement of insulin is inherently difficult to achieve with open-loop subcutaneously administered insulin, the continued development of improved injectable insulin formulations with superior pharmacokinetics and pharmacodynamics will enhance glucose control, and represents important clinical advances in the treatment of both type 1 and type 2 diabetes.