Confined chorionic mosaicism, a discordance in the karyotype between the fetus and placenta, occurs in 1% of chorionic villus sampling (CVS) cases. While the cytogenetic discrepancies occurring between different fetal tissues may pose clinical dilemmas, they can also be viewed as a natural experiment to determine early cell lineage relationships in the human. We reviewed extensive data in experimental animals to define the origin of the human extraembryonic mesoderm. The extraembryonic mesoderm in humans is an important component of the CVS culture preparation. Previously, the extraembryonic mesoderm was thought to originate in the cytotrophoblast or primitive streak. More recent evidence supports its origin from the yolk sac, which does not always correlate with the fetal karyotype. We formulated a model of early human cell lineage and employed it to clarify clinical cases of chorionic mosaicism in two large published studies.