Since the first diabetic was treated with insulin in 1922, millions of patients have relied on frequent insulin injections and glucose monitoring to combat the disease and its complications. Improved immunosuppressive regimens in islet transplantation developed in the Edmonton protocol raised the hopes of diabetics worldwide for a complete cure and insulin independence. However, transplant success has proven to be short-lived and accompanied by significant side effects. Using a clever genetic model for conditional ablation of pancreatic beta cells in vivo, Nir and colleagues show in this issue of the JCI that the immunosuppressant drugs clinically inhibit beta cell proliferation in the diabetic setting (see the related article beginning on page 2553). They also demonstrate that beta cells have a remarkable regenerative capacity and that normal beta cell mass can recover even in the setting of hyperglycemia. Their new mouse model should aid in the development of improved immunoregulatory strategies and in the elucidation of the molecular pathways that govern beta cell regeneration.