The c-mos proto-oncogene encodes a 37-39K cytoplasmic serine/threonine kinase implicated in the meiotic maturation events during murine spermatogenesis and oogenesis. In Xenopus, ectopic expression of pp39mos can promote both the meiotic maturation of oocytes and also arrest the cleavage of blastomeres. To elucidate the role of pp39mos we have generated homozygous mutant mice by gene targeting in embryonic stem cells. These mice are viable and mutant males are fertile, demonstrating that pp39mos is not essential for spermatogenesis. In contrast, mutant females, have a reduced fertility because of the failure of mature eggs to arrest during meiosis. c-mos-/- oocytes undergo germinal vesicle breakdown and extrusion of both polar bodies followed in some cases by progression into cleavage. Mutant females also develop ovarian cysts. These results demonstrate that a major role for pp39mos is to prevent the spontaneous parthenogenetic activation of unfertilized eggs.