The mitotic-to-meiotic transition during spermatogenesis is essential for generating haploid spermatid cells from diploid spermatogonial cells. After differentiation and proliferation of spermatogonial cells, two rounds of meiosis are required to generate spermatid cells, but how the complex transition from mitosis to meiosis is coordinated remains unclear. In this issue (p. 3662), David Zarkower and colleagues investigate the role of the Doublesex-related gene Dmrt6 in male mouse spermatogenesis and show that without DMRT6 this process is severely compromised. By creating a null mutation in two different genetic backgrounds, the authors provide strong evidence that DMRT6 is required for spermatogonial differentiation (C57BL/6J strain) and meiosis (129Sv strain) and that inappropriate gene expression and chromatin events occur when DMRT6 activity is absent. Subsequent mRNA profiling and chromatin precipitation experiments suggest that DMRT6 functions both to suppress genes that promote spermatogonial differentiation and to activate important meiotic regulatory genes. These data provide novel insight into the molecular regulatory events that control and coordinate the mitotic-to-meiotic transition during mammalian spermatogenesis.