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One of the earliest studies on human pancreas regeneration dates from the beginning of the 1900s when the American pathologist Russel Cecil noted signs of attempted islet regeneration in samples from organ donors with diabetes. A century later, the quest is on to enhance the limited regenerative potential of the pancreas in order to develop new therapies for diabetes. While regeneration is incomplete in mammals, zebrafish can naturally recover from extreme β-cell destruction and hyperglycemia by producing new β-cells. Here, we discuss how a unique blend of in vivo imaging, genetics and drug discovery in zebrafish could reveal the secrets of natural β-cell regeneration. Specifically, we explore the essential steps for successful regeneration, from the induction of pancreas plasticity to the integration of cells into networks that establish functional islet communities.