The transcription factor Oct4 is well known for its role in maintaining pluripotency in vitro and for preventing ectopic differentiation of early embryos in vivo. Recent evidence also suggests a role for Oct4 in lineage specification; however, little is known about how this occurs and the manner in which Oct4 is required. Now, on p. 1001, Jennifer Nichols and colleagues report a non-cell-autonomous requirement for sustained Oct4 expression during primitive endoderm (PrE) specification. The authors confirm that maternal and zygotic Oct4 are not required for development to the blastocyst stage, but that conditional inactivation of Oct4 in the early blastocyst results in reduced expression of PrE markers Sox17 and Gata4, and a failure to generate PrE-derived tissue in chimeric assays. Surprisingly, the formation of PrE can be rescued if the conditionally inactivated Oct4 mutants are injected at the pre-blastocyst stage with wild-type embryonic stem cells, suggesting that Oct4 is not required to operate cell-autonomously in order to specify the PrE.