This review considers the role of α-cells in β-cell generation and regeneration. We describe recent evidence obtained from lineage-tracing studies showing that α-cells can serve as progenitors of β-cells and present a hypothetical model how injured β-cells might activate α-cells in adult islets to promote β-cell regeneration. β-cells appear to arise by way of their trans-differentiation from undifferentiated α progenitor cells, pro-α-cells, both during embryonic development of the islets and in the adult pancreas in response to β-cell injuries. Plasticity of α-cells is endowed by the expression of the gene encoding proglucagon, a prohormone that can give rise to glucagon and glucagon-like peptides (GLPs). The production of glucagon from proglucagon is characteristic of fully-differentiated α-cells whereas GLP-1 becomes a product of undifferentiated α-cells. GLP-1, a cell growth and survival factor, is proposed to promote the expansion of undifferentiated pro-α-cells during development. β-cells arise from pro-α-cells by a change in the relative amounts of the transcription factors Arx and Pax4, master regulators of the α- and β-cell lineages, respectively. A paracrine/autocrine model is proposed whereby injuries of β-cells in adult islets induce the production and release of factors, such as stromal cell-derived factor-1, that cause the de-differentiation of adjacent α-cells into pro-α-cells. Pro-α-cells produce GLP-1 and its receptor that renders them competent to trans-differentiate into β-cells. The trans-differentiation of pro-α-cells into β-cells provides a potentially exploitable mechanism for the regeneration of β-cells in individuals with type 1 diabetes.