Pancreatic β-cells are the sole source of insulin, the major hormonal regulator of glycaemia. In physiological and pathological conditions with increased insulin demand, β-cells adjust their insulin output either through increased insulin secretory granule (ISG) biogenesis and secretion, or hyperplasia. Failure of these compensatory mechanisms eventually results in hyperglycaemia and diabetes mellitus. Both of these major adaptive behaviours are positively regulated by several extrinsic factors, such as glucose, GLP-1, insulin and growth hormones (GH). Still unclear, however, it is how β-cells in response to these stimuli opt for one or the other strategy at a given time. Here we review recent advances concerning the factors and pathways that enhance ISG biogenesis and β-cell replication, and propose the existence of ‘switch factors' that play a key role in regulating the shift between these two adaptive responses.