Pancreatic β-cell expansion and functional maturation during the birth-to-weaning period plays an essential role in the adaptation of plasma insulin levels to metabolic needs. These events are driven by epigenetic programs triggered by growth factors, hormones, and nutrients. These mechanisms operating in the neonatal period can be at least in part reactivated in adult life to increase the functional β-cell mass and face conditions of increased insulin demand such as obesity or pregnancy. In this review, we will highlight the importance of studying these signaling pathways and epigenetic programs to understand the causes of different forms of diabetes and to permit the design of novel therapeutic strategies to prevent and treat this metabolic disorder affecting hundreds of millions of people worldwide.