The Cdk8 kinase and associated proteins form a nonessential transcriptional repressor module of the Mediator in the budding yeast Saccharomyces cerevisiae. Genetic analyses of this module have demonstrated functions ranging from environmental responses in budding yeast to organogenesis and development in worms, flies, and zebrafish. Here we have investigated the function of mammalian Cdk8 using mice harboring a gene trap insertion at the Cdk8 locus inactivating this kinase. No phenotypes were noted in heterozygote Cdk8(+/-) mice, but intercrossing these did not produce homozygous Cdk8(-/-) offspring. Developmental analysis demonstrated a requirement for Cdk8 prior to implantation at embryonic days 2.5 to 3.0. Cdk8(-/-) preimplantation embryos had fragmented blastomeres and did not proceed to compaction. As Cdk8 deficiency in cultured metazoan cells did not affect cell viability, the results suggest that transcriptional repression of genes critical for early-cell-fate determination underlies the requirement of Cdk8 in embryogenesis.