Pancreatic β-cell mass adapts to changing insulin demands in the body. One of the most amazing reversible β-cell adaptations occurs during pregnancy and postpartum conditions. During pregnancy, the increase in maternal insulin resistance is compensated by maternal β-cell hyperplasia and hyperfunctionality to maintain normal blood glucose. Although the cellular mechanisms involved in maternal β-cell expansion have been studied in detail in rodents, human studies are very sparse. A summary of these studies in rodents and humans is described below. Since β-cell mass expands during pregnancy, unraveling the endocrine/paracrine/autocrine molecular mechanisms responsible for these effects can be of great importance for predicting and treating gestational diabetes and for finding new cues that induce β-cell regeneration in diabetes. In addition to the well known implication of lactogens during maternal β-cell expansion, additional participants are being discovered such as serotonin and HGF. Transcription factors, such as hepatocyte nuclear factor-4α and the forkhead box protein-M1, and cell cycle regulators, such as menin, p27 and p18, are important intracellular signals responsible for these effects. In this article, we summarize and discuss novel studies uncovering molecular mechanisms involved in the maternal β-cell adaptive expansion during pregnancy.