Pancreatic β-cell mass exhibits plasticity under conditions of physiological metabolic challenge such as pregnancy, and in the presence of hyperglycemia and obesity. A failure of compensation can contribute to the onset of diabetes. Mechanistic models of β-cell plasticity can teach us much about the potential for targeted beta cell regeneration, and how this may alter with age. A key question is the identification of the cellular source(s) of β-cell expansion and, secondly, the nature of the stimuli that activate either a normally quiescent beta cell population or the differentiation of β-cell progenitors resident within the pancreas. Adult beta cells have a very low rate of proliferation, and the ability to generate new cells by neogenesis from pancreatic ducts, or by trans-differentiation from other islet endocrine cells, ceases shortly after birth. During metabolic stress, growth-arrested beta cells can re-enter the cell cycle due to a reduced expression of cell cycle inhibitory proteins, particularly in an immature population of β-cells that are normally resident in the small, but highly abundant, extra-islet endocrine clusters. These may contribute little to insulin release but represent a reserve of proliferative plastic cells with multiple lineage potential from which to increase functional β-cell mass. The triggers to mobilization of β-cell progenitors and reactivation of β-cell proliferation include metabolic, endocrine and paracrine stimuli. Modulation of these pathways could represent exploitable strategies for the regeneration of β-cell mass to prevent or reverse diabetes.