Stem cell maintenance involves both intrinsic factors produced by the stem cells and extrinsic factors produced by their microenvironment. Dahua Chen and colleagues have been investigating the poorly understood intrinsic mechanisms that repress the differentiation of germline stem cells (GSCs) in Drosophila and now report that the proper control of cell mitosis is essential for stem cell maintenance (see p. 4133). The researchers first show that the eff gene, which encodes an E2 ubiquitin-conjugating enzyme (Eff), is essential for GSC maintenance. Eff, they report, interacts with the anaphase-promoting complex/cyclosome, a multisubunit E3 ligase that targets mitotic regulators for degradation during the cell cycle. Furthermore, the expression of a stable form of the mitotic regulator Cyclin A results in the loss of GSCs. Thus, the researchers suggest, Eff-mediated degradation of Cyclin A (and probably other mitotic cyclins) is essential for GSC maintenance in Drosophila and, because the regulation of mitotic cyclins is evolutionarily conserved, a similar mechanism might maintain stem cells in mammals.