Anterior-posterior (A-P) patterning is of fundamental importance throughout vertebrate embryonic development. Murine members of the trithorax (trx) and Polycomb group (Pc-G) of genes regulate A-P patterning of segmented axial structures, demonstrating conserved upstream regulation of homeotic pathways between Drosophila and mouse. Here we report the positional cloning of a classical mouse mutation, eed (for embryonic ectoderm development), which is the highly conserved homologue of the Drosophila Pc-G gene esc (for extra sex combs), a long-term repressor of homeotic genes. Mutants homozygous for a null allele of eed display disrupted A-P patterning of the primitive streak during gastrulation. Mutant embryos lack a node, notochord and somites, and there is no neural induction. In contrast to absence of anterior structures, extra-embryonic mesoderm is abundant. Mice carrying a hypomorphic eed mutation exhibit posterior transformations along the axial skeleton. These results indicate that eed is required globally for A-P patterning throughout embryogenesis.