A reliable method for generating insulin-producing β-cells from human pluripotent stem cells (hPSCs) would provide new therapeutic options for people with diabetes. So far, no-one has developed such a method but, on p. 861, Gordon Keller and colleagues provide new insights into the complex signalling networks that underlie β-cell differentiation. The generation of β-cells from hPSCs requires efficient endoderm induction followed by patterning and specification to a pancreatic fate. The researchers show that the duration of nodal/activin A signalling plays a pivotal role in endoderm induction and that WNT signalling enhances the subsequent development of pancreatic lineage cells. Inhibition of BMP signalling at specific stages is also essential for the generation of insulin-expressing cells. Importantly, report the researchers, optimal stage-specific manipulation of TGFβ and WNT signalling yields cell populations that produce insulin at levels similar to those made by the pancreas. However, because these cells also make other hormones, further studies are needed to discover how to convert these polyhormonal cells into functional β-cells.