Retinoblastoma is a rare pediatric cancer that has served as a paradigm to investigate the mechanisms of tumorigenesis. In this issue of Genes & Development, Conkrite and colleagues (pp. 1734-1745) found high levels of the miR-17~92 and miR-106b-25 microRNAs in primary retinoblastomas and show that overexpression of miR-17~92 accelerates retinoblastoma development in mice by promoting proliferation, in part by reducing expression of the cell cycle inhibitor p21. These experiments identify the RB/miR-17~92/p21 axis as a critical regulator of retinoblastoma tumorigenesis and potentially many other cancers.