Doug Melton and colleagues (Cell 153, 747–758, 2013) report the discovery of a secreted peptide produced by liver and fat cells that stimulates the proliferation of pancreatic β cells. The authors discovered this putative hormone, which they call betatrophin, by studying a new mouse model in which insulin resistance is induced by administering the insulin receptor antagonist S961. They found that mice infused with S961 showed a striking increase in β cell proliferation, whereas mouse β cells treated directly in vitro with S961 showed no effect. To look for potential mediators of the in vivo stimulatory activity of S961, the authors performed an expression screen in tissues involved in metabolic regulation and found that the gene encoding betatrophin was upregulated in liver and fat cells following S961 treatment in the insulin resistance model as well as in other diabetic models. They further showed that betatrophin is a secreted protein that is conserved in mammals and detectable in human serum. Notably, when they injected betatrophin expression constructs into mouse liver, they observed a dramatic increase in β cell proliferation, β cell mass and insulin production. Future work will now be aimed at testing the activity of recombinant betatrophin protein and elucidating downstream signaling mechanisms.