Maternal DNA methylation by DNA methyltransferase 3A (DNMT3A) and DNMT3B has an important yet uncharacterized role in the development of trophoblast (extra-embryonic) tissues. Branco et al. generated maternal, oocyte-specific Dnmt3a and Dnmt3b double-knockout (mDKO) mice and found pronounced reduction in the adhesion of trophoblast giant cells in mDKO conceptuses, with direct effects on the expression of trophoblast differentiation and adhesion genes. Cultured Dnmt-null trophoblast stem cells (TSCs) formed less-distinct colonies with decreased surface adherence and exhibited gene expression changes similar to those in mDKO early trophoblasts. Scml2, encoding a subunit of Polycomb repressive complex 1, was highly upregulated in both Dnmt-null cell types and responsible for downregulation of a placenta morphogenesis marker. Scml2 deletion in Dnmt-null TSCs restored their surface adherence. Thus, oocyte-derived DNA methylation is essential for placental development.