NR5A2 is an orphan nuclear hormone receptor that has diverse developmental and physiological functions. It is expressed in the inner cell mass of early mouse embryos and in the developing endoderm, but its role in organogenesis is unclear. Here, Ray MacDonald and co-workers reveal a crucial role for NR5A2 during pancreatic development in mice (p. 3123). They first show that Nr5a2 is highly expressed in multipotent progenitor cells (MPCs), which give rise to endocrine, acinar and ductal cells, and in pre-MPCs, consistent with a role for NR5A2 in MPC formation. Indeed, pancreas-specific inactivation of Nr5a2 greatly diminishes the number of MPCs, and the development of all three lineages is affected. Subsequently, the researchers report, Nr5a2 expression is maintained in pre-acinar, acinar and ductal cells but is reduced in islet cells, suggesting that it regulates the development of the acinar lineage. In line with this, acinar morphogenesis was shown to be defective in an NR5A2-deficient pancreas. Furthermore, gene expression analyses indicate that NR5A2 can directly and indirectly modulate the expression of many genes involved in acinar differentiation and cell cycle control as well as in branching morphogenesis. These results demonstrate that NR5A2 controls multiple aspects of pancreas development and suggest that the experimental modulation of NR5A2 activity could be used to strategically direct the formation of pancreatic β-cells in vitro.