Introduction: Tremendous progress has been made in generating insulin-producing cells from pluripotent stem cells. The best outcome of the refined protocols became apparent in the first clinical trial announced by ViaCyte, based on the implantation of pancreatic progenitors that would further mature into functional insulin-producing cells inside the patients body.Areas covered: Several groups, including ours, have contributed to improve strategies to generate insulin-producing cells. Of note, the latest results have gained a substantial amount of interest as a method to create a potentially functional and limitless supply of β-cell to revert diabetes mellitus. This review analyzes the accomplishments that have taken place over the last few decades, summarizes the state-of-art methods for β-cell replacement therapies based on the differentiation of embryonic stem cells into glucose-responsive and insulin-producing cells in a dish and discusses alternative approaches to obtain new sources of insulin-producing cells.Expert opinion: Undoubtedly, recent events preface the beginning of a new era in diabetes therapy. However, in our opinion, a number of significant hurdles still stand in the way of clinical application. We believe that the combination of the private and public sectors will accelerate the process of obtaining the desired safe and functional β-cell surrogates.