Because type 1 and type 2 diabetes are characterized by loss of β-cells, β-cell regeneration has garnered great interest as an approach to diabetes therapy. Here, we developed a new model of β-cell regeneration, combining pancreatic duct ligation (PDL) with elimination of pre-existing β-cells with alloxan. In this model, in which virtually all β-cells observed are neogenic, large numbers of β-cells were generated within 2 weeks. Strikingly, the neogenic β-cells arose primarily from α-cells. α-cell proliferation was prominent following PDL plus alloxan, providing a large pool of precursors, but we found that β-cells could form from α-cells by direct conversion with or without intervening cell division. Thus, classical asymmetric division was not a required feature of the process of α- to β-cell conversion. Intermediate cells coexpressing α-cell- and β-cell-specific markers appeared within the first week following PDL plus alloxan, declining gradually in number by 2 weeks as β-cells with a mature phenotype, as defined by lack of glucagon and expression of MafA, became predominant. In summary, these data revealed a novel function of α-cells as β-cell progenitors. The high efficiency and rapidity of this process make it attractive for performing the studies required to gain the mechanistic understanding of the process of α- to β-cell conversion that will be required for eventual clinical translation as a therapy for diabetes.