Insulin is a peptide hormone essential for maintaining normal blood glucose levels. Individuals unable to secrete sufficient insulin or not able to respond properly to insulin develop diabetes. Since the discovery of insulin its structure and function has been intensively studied with the aim to develop effective diabetes treatments. The three-dimensional crystal structure of this 51 amino acid peptide paved the way for discoveries, outlined in this review, of determinants important for receptor binding and hormone stability that have been instrumental in development of insulin analogs used in the clinic today. Important for the future development of effective diabetes treatments will be a detailed understanding of the insulin receptor structure and function. Determination of the three-dimensional structure of the insulin receptor, a receptor tyrosine kinase, proved challenging but with the recent advent of high-resolution cryo-electron microscopy significant progress has been made. There are now >40 structures of the insulin:insulin receptor complex deposited in the Protein Data Bank. From these structures we have a detailed picture of how insulin binds and activates the receptor. Still lacking are details of the initial binding events and the exact sequence of structural changes within the receptor and insulin. In this review, the focus will be on the most recent structural studies of insulin:insulin receptor complexes and how they have contributed to the current understanding of insulin receptor activation and signaling outcome. Molecular mechanisms underlying insulin receptor signaling bias emerging from the latest structures are described.Copyright © 2023 Elsevier Inc. All rights reserved.