The self-renewing ability of stem cells is crucial in many developmental contexts; however, the mechanisms that regulate the switch between proliferation and differentiation are poorly understood. Spermatogonial stem cells (SSCs) provide an excellent model in which to study self-renewal as large numbers of stem cells can be expanded in culture and the markers that characterise these cells are well defined. On p. 1853, Shinohara and colleagues reveal a crucial role for the phosphoinositide-3 kinase(PI3K)-Akt pathway in mouse SSC self-renewal. Glial cell line-derived neurotrophic factor (GDNF) has previously been shown to regulate the self-renewal of SSCs in culture via downstream signals that have yet to be fully elucidated. Now these authors show that Akt is phosphorylated in the presence of GDNF and that this activated Akt can maintain SSC self-renewal in culture for several months; this self-renewal capacity can be inhibited by a chemical inhibitor of PI3K. Whether these insights can be applied to other tissue-specific stem cells remains to be determined.