What is the evolutionary origin of pluripotent stem cells? On p. 2429, Uri Frank and colleagues provide new insights into this longstanding question by studying the marine cnidarian Hydractinia echinata. In mammals, pluripotent stem cells are limited to early embryos where they are induced and maintained by the POU domain protein Oct4 and certain other key transcription factors. By contrast, clonal invertebrates such as H. echinata possess pluripotent stem cells throughout their life. Here, Frank and colleagues report that Polynem (Pln), a putative homologue of Oct4, is expressed in the embryonic and adult stem cells of H. echinata and that ectopic expression of Pln in epithelial cells induces stem cell neoplasms and loss of epithelial tissue. Neoplasm cells, they report, downregulate expression of the Pln transgene but express the endogenous Pln gene and other cnidarian stem cell markers. Conversely, Pln downregulation by RNAi leads to differentiation of adult stem cells. Together, these results suggest that POU proteins are conserved regulators of stem cells.