The primitive erythroid (PrE) lineage is the first mammalian blood cell lineage to form - in the embryonic yolk sac from its hemangioblast precursor -but little is known about the signals that specify it, or how it is regulated(primitive erythropoiesis occurs for just 48 hours). Gordon Keller and colleagues now employ an ES cell differentiation approach (see p. 3447) to investigate the involvement of Wnt and Notch signalling in PrE specification. By inducing genes and by assaying transcriptional activity and differentiation markers in ES cells, they have discovered that canonical Wnt signalling,together with Notch pathway inhibition by Numb, is required for an in vitro hemangioblast equivalent to differentiate specifically into the PrE lineage. By contrast, Notch signalling inhibits primitive erythropoiesis by upregulating Wnt pathway inhibitors. Of particular interest, the authors report, is the rapid downregulation of Wnt signalling, which suggests that just a short period of Wnt activity is required to establish the PrE fate,which might in turn underlie the transient nature of primitive erythropoiesis.