Loss of genomic integrity in preimplantation embryos can cause not only developmental arrest but also diseases such as congenital disorders and cancers. However, the key factors for maintaining genomic integrity in preimplantation embryos remain unknown. Shikata et al. reported that SETD8-mediated monomethylation of H4K20, a type of epigenetic modification, plays an important role in the maintenance of genomic integrity (Shikata et al. H4K20 monomethylation inhibition causes loss of genomic integrity in mouse preimplantation embryos. pp. 411–419). In our study, the inhibition of SETD8 or the overexpression of dominant-negative histone H4 mutants resulted in developmental arrest and excessive accumulation of DNA double-strand breaks, suggesting that H4K20 monomethylation is associated with DNA damage repair and is essential for preimplantation development.