Cell therapy is currently considered as a potential therapeutic alternative to traditional treatments of diabetes. Islet and whole pancreas transplantations provided the proof-of-concept of glucose homeostasis restoration after replenishment of the deficiency of β cells responsible for the disease. Current limitations of these procedures have led to the search for strategies targeting replication of pre-existing β cells or transdifferentiation of progenitors and adult cells. These investigations revealed an unexpected plasticity towards β cells of adult cells residing in pancreatic epithelium (eg, acinar, duct, and α cells). Here we discuss recent developments in β-cell replication and β-cell transdifferentiation of adult epithelial pancreatic cells, with an emphasis on techniques with a potential for clinical translation.