Identical (monozygotic) twins are born at a rate of 3–4 per 1000 births worldwide. They arise when an embryo splits, presumably within 2 weeks after conception. How often and why this occurs in human pregnancies is unknown: the event cannot be observed in vivo and might be more common than typically recognized due to vanishing twin syndrome. Monozygotic twinning may be an overlooked cause of certain congenital malformations of unknown etiology, such as amyoplasia and Beckwith–Wiedemann syndrome, for which a greatly increased frequency of monozygotic twins has been noted among patients. In this chapter, we review what is known about monozygotic twinning in humans after natural conception and medically assisted reproduction (MAR), and discuss recent developments in model systems to study early human embryonic development.