The endoderm gives rise to diverse tissues and organs that are essential for the homeostasis and metabolism of the organism: the thymus, thyroid, lungs, liver and pancreas, and the functionally diverse domains of the digestive tract. Classically, the endoderm, the 'innermost germ layer', was in the shadow of the ectoderm and mesoderm. However, at a recent Keystone meeting it took center stage, revealing astonishing progress in dissecting the mechanisms underlying the development and malfunction of the endodermal organs. In vitro cultures of stem and progenitor cells have become widespread, with remarkable success in differentiating three-dimensional organoids, which - in a new turn for the field - can be used as disease models.