Small RNAs associate with Argonaute proteins and serve as sequence-specific guides for regulation of mRNA stability, productive translation, chromatin organization, and genome structure. In animals, the Argonaute superfamily segregates into two clades. The Argonaute clade acts in RNAi and in microRNA-mediated gene regulation in partnership with 21-22 nt RNAs. The Piwi clade, and their 26-30 nt piRNA partners, have yet to be assigned definitive functions. In mice, two Piwi-family members have been demonstrated to have essential roles in spermatogenesis. Here, we examine the effects of disrupting the gene encoding the third family member, MIWI2. Miwi2-deficient mice display a meiotic-progression defect in early prophase of meiosis I and a marked and progressive loss of germ cells with age. These phenotypes may be linked to an inappropriate activation of transposable elements detected in Miwi2 mutants. Our observations suggest a conserved function for Piwi-clade proteins in the control of transposons in the germline.