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Crossing over during meiotic prophase I is required for sexual reproduction in mice and contributes to genome-wide genetic diversity. Here we report on the characterization of an N-ethyl-N-nitrosourea-induced, recessive allele called mei4, which causes sterility in both sexes owing to meiotic defects. In mutant spermatocytes, chromosomes fail to congress properly at the metaphase plate, leading to arrest and apoptosis before the first meiotic division. Mutant oocytes have a similar chromosomal phenotype but in vitro can undergo meiotic divisions and fertilization before arresting. During late meiotic prophase in mei4 mutant males, absence of cyclin dependent kinase 2 and mismatch repair protein association from chromosome cores is correlated with the premature separation of bivalents at diplonema owing to lack of chiasmata. We have identified the causative mutation, a transversion in the 5′ splice donor site of exon 1 in the mouse ortholog of Human Enhancer of Invasion 10 (Hei10; also known as Gm288 in mouse and CCNB1IP1 in human), a putative B-type cyclin E3 ubiquitin ligase. Importantly, orthologs of Hei10 are found exclusively in deuterostomes and not in more ancestral protostomes such as yeast, worms, or flies. The cloning and characterization of the mei4 allele of Hei10 demonstrates a novel link between cell cycle regulation and mismatch repair during prophase I., Author Summary Human infertility and reproductive complications have devastating social and monetary costs. Errors in meiosis during reproduction may lead to birth defects, spontaneous abortion, or infertility. Many of the genes essential for meiosis function in DNA repair and mutations in several of these genes have been shown to contribute to cancer. The identification of the genes necessary for normal meiosis is an important goal and will potentially influence the fields of reproductive and cancer biology. In this study, genetic screens in mice have generated the mutation mei4. mei4 causes male and female sterility by disrupting meiosis and altering the function of the DNA repair system known as mismatch repair. We have identified the causative mutation behind the mei4 phenotype in a gene called Human Enhancer of Invasion 10 or Hei10. This work demonstrates that Hei10 is essential for the completion of meiosis and that it functions to coordinate the DNA repair system and the progression of the cell cycle during meiosis.