Insulin is a key regulator of life. Until 25 years ago, the pancreatic beta-cell was thought to be the only organ that produces insulin in the body. Insulin deficiency, whether absolute (in type 1) or relative (in type 2 diabetes), underlies the metabolic derangements in diabetes mellitus, and investigations on insulin have concentrated on pancreatic insulin production, its regulation and the metabolic consequences of insulin deficiency. The thymus was the next organ that was found to also produce insulin, a process that may tolerize the body to the molecule, protecting the host from developing autoimmune beta-cell destruction and (type 1) diabetes. However, now and then there were descriptions of promiscuous insulin production outside the pancreas. During our investigations on diabetes gene therapy in rodents, we serendipitously came across the presence of mysterious cells marked by proinsulin production in unexpected organs, some of which cells may underlie certain chronic diabetic complications. Starting with a historical perspective on insulin expression in brain and thymus, this review focuses mainly on unraveling the mystery of extrapancreatic extrathymic proinsulin/insulin expression in diabetes mellitus.