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Understanding organ development and achieving functional restoration of diseased organs is a broad goal motivating effort in our group. Pancreatic islets of Langerhans, endocrine organs that secrete insulin and glucagon, have emerged as a paradigm for investigating both organ development and restoration. Deficiency of insulin-producing islet β-cells or their function underlies the pathogenesis of diabetes mellitus, a disease with devastating autoimmune (type 1), pandemic (type 2), and exocrine-associated (type 3c) forms. However, islet replacement, or preservation in diabetes, is ultimately limited by our inadequate understanding of mechanisms controlling islet formation, growth and immunological protection. To discover these mechanisms, my laboratory is using a combination of genetic, developmental, immunological, physiological and genomic approaches in different experimental systems, with a focus on several fundamental questions: What are the cellular, molecular, signaling and genetic mechanisms regulating pancreatic development and functional maturation? Can we harness our growing understanding of pancreatic islet development to generate replacement islets for diabetes, including islet cells generated from human stem cell lines? What are the genetic programs underlying diabetes risk? What immunological and transplantation paradigms can be developed to protect native or replacement islets in type 1 diabetes? Can we advance understanding of normal pancreas development and function to discover the basis of devastating exocrine pancreatic diseases, including pancreatic cancer?To address these challenges, our group has developed new approaches in mice, fruit flies, pigs, primary human pancreatic cells, and multipotent human stem cells. Each of these systems offers different experimental advantages. Discoveries from our systems have created unprecedented opportunities for harnessing knowledge about pancreatic development and growth to restore pancreas islet function, and to identify the molecular, genetic, signaling, and immune basis of pancreatic diseases like diabetes mellitus, pancreatitis and pancreatic cancer.