Three mouse homologues of the Drosophila homeotic gene Caudal (Cad) have been described. They are currently designated Cdx-1, Cdx-2, and Cdx-4. Cdx-1 and 2 are both strongly expressed in the adult mid- and hindgut, while Cdx-1 and 4 have been shown to be activated in the embryonic primitive streak. Using a polyclonal antibody against a fusion protein containing the amino terminal 109 amino acids of murine Cdx-2, we here describe the topographical location of the gene product from early cleavage to 12.5 days of embryonic development. Cdx-2 expression begins at 3.5 days and is confined to the trophectoderm, being absent from the inner cell mass. Subsequently, staining is located in the extra-embryonic ectoderm adjacent to the epiblast, but sparing the more superficially placed polar, as well as the mural trophoblastic cells. Continuing expression in the fetal membranes involves the chorion, the allantoic bud, and, at even later stages, the spongiotrophoblast. From 8.5 days, Cdx-2 begins to be expressed in embryonic tissues, principally (unlike Cdx-1) in the posterior part of the gut from its earliest formation, as well as in the tail bud and in the caudal part of the neural tube. Cdx-2 is, therefore, transcribed well before any other membrane of the Cad homologue group and of the related Hox-C group; its expression in the extra-embryonic membranes and in the hindgut reflects the phylogenetic relationship between the cloaca and the chorio-allantois and suggests the possibility that homeobox genes may be involved in placental development and/or patterning.