The identification of a “rundlichen Häuflein” by Paul Langerhans more than 150 years ago marked the initiation of a global effort to unravel the mysteries of pancreatic islets, an intricate system of nutrient-sensing, hormone-secreting, and signaling cells. In type 1 diabetes, this interconnected network is vulnerable to malfunction and immune attack, with strategies to prevent or repair islet damage still in their infancy. In 2014, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established the Human Islet Research Network (HIRN) to accelerate our understanding of the molecular and cellular basis of type 1 diabetes development. In this article, investigators from the HIRN detail pioneering advances, technologies, and systems that contextualize insulin-producing β-cells and other related cells within their physiological environment. Disease models, devices, and therapies are evaluated by the HIRN in light of promising functional and mechanistic data. Collaborative relationships and opportunities within this network are emphasized as a means of enhancing the quality of innovative research and talent in science. Topics are developed through a series of questions, achievements, and milestones, with the 75th anniversary of the NIDDK as an opportunity to reflect on the past, present, and future of type 1 diabetes research. Article Highlights The Human Islet Research Network (HIRN) was created by the National Institute of Diabetes and Digestive and Kidney Diseases to accelerate pioneering basic and translational research on the prevention, development, and progression of type 1 diabetes. There are critical knowledge gaps in research on the processes underlying human β-cell protection, loss, and replacement in type 1 diabetes. A multidisciplinary and collaborative research community focused on outstanding biological questions propels the development of innovative models, tools, and technologies and helps contextualize the complexity of this disease. Discoveries arising from the HIRN will profoundly improve our understanding of type 1 diabetes pathogenesis and expedite the development of disease avoidance, diagnosis, and treatment strategies.