Transplantation of allogeneic islets can correct the metabolic abnormalities of Type I diabetes. Limited availability of donor pancreas tissues restricts the application of this therapeutic modality to a subset of eligible recipients. In an attempt to expand the utility of available donor human pancreas tissue, we developed a method to stimulate the proliferation of insulin-secreting beta-cells within human islets. A lentiviral vector was used to introduce into human islets chimeric signaling receptors that are activated to stimulate cell proliferation through interactions with a small-molecule drug called a chemical inducer of dimerization (CID). In vitro exposure of vector-transduced human islets to the CID expanded the number of cells and increased regulated insulin secretion. Transplantation of the regenerated islets into diabetic immunodeficient mice, followed by in vivo administration of the CID, corrected hyperglycemia. This strategy has the potential to reduce the quantity of human islets required for treatment of patients with Type I diabetes.