Canonical Wnt/β-catenin signalling is required for the formation of the primitive streak (PS), mesoderm and endoderm during early vertebrate embryogenesis. Now, using an in vitro model that recapitulates early human embryogenesis, Sumi and colleagues show that Wnt/β-catenin signalling cooperates with Activin/Nodal and BMP signalling to direct the early lineage specification of human embryonic stem cells (hESCs; see p. 2969). The stabilized expression of β-catenin, they report, perturbs hESC self-renewal and results in 80% of hESCs developing into posterior PS/mesoderm progenitors. The Wnt/β-catenin and BMP signalling pathways, they reveal,cooperate to establish these progenitors because blockade of BMP signalling diverts the hESCs to an anterior PS/endoderm fate. Activin/Nodal and Wnt/β-catenin signalling, however, synergistically induce hESC differentiation into anterior PS/endoderm progenitors. Thus, the balance of Activin/Nodal and BMP signalling defines the cell fate of the nascent PS cells that are induced by canonical Wnt/β-catenin signalling in hESCs. This information, the researchers suggest, could facilitate the production of specific cell types from hESCs for transplantation.