ABSTRACTThe placenta is essential for reproductive success. The murine placenta includes polyploid giant cells that are crucial for its function. Polyploidy occurs broadly in nature but its regulators and significance in the placenta are unknown. We have discovered that many murine placental cell types are polyploid and have identified factors that license polyploidy using single-cell RNA sequencing.Mycis a key regulator of polyploidy and placental development, and is required for multiple rounds of DNA replication, likely via endocycles, in trophoblast giant cells. Furthermore, MYC supports the expression of DNA replication and nucleotide biosynthesis genes along with ribosomal RNA. Increased DNA damage and senescence occur in trophoblast giant cells withoutMyc, accompanied by senescence in the neighboring maternal decidua. These data revealMycis essential for polyploidy to support normal placental development, thereby preventing premature senescence. Our study, combined with available literature, suggests thatMycis an evolutionarily conserved regulator of polyploidy.