When primary murine fibroblasts are placed in culture they exhibit replicative senescence, associated with the induction of cell-cycle inhibitors. The Ink4a-Arf locus encodes two proteins, p16^Ink4a and p19^Arf, which regulate the cell cycle by modulating the activities of pRb and p53, respectively. In the Early Edition of the Proceedings of the National Academy of Sciences, Randle et al. describe the role of p19^Arf in preventing immortalization of bone-marrow-derived preB cells and macrophages (Proc Natl Acad Sci USA, 10.1073/pnas.171217498). PreB cells from Arf-null mice evaded the senescence observed in wild-type cells and continued to express high levels of p16^Ink4a. But Arf-null macrophages lost p16^Ink4a during the immortalization process, by methylation-suppression of the Ink4a promoter. Wild-type macrophages also lost p16^Ink4a expression in established lines. The authors conclude that loss of the two Ink4a-Arf transcripts has different effects on senescence of preB cells or macrophages.