β-Cell replacement by in situ reprogramming of non-β-cells is a promising diabetes therapy. Following the observation that near-total β-cell ablation in adult mice triggers the reprogramming of pancreatic α-, δ-, and γ-cells into insulin (INS)-producing cells, recent studies are delving deep into the mechanisms controlling adult α-cell identity. Systematic analyses of the α-cell transcriptome and epigenome have started to pinpoint features that could be crucial for maintaining α-cell identity. Using different transgenic and chemical approaches, significant advances have been made in reprogramming α-cells in vivo into INS-secreting cells in mice. The recent reprogramming of human α-cells in vitro is an important step forward that must now be complemented with a comprehensive molecular dissection of the mechanisms controlling α-cell identity.