The INK4a/ARF locus encodes two unrelated tumor suppressor proteins, p16INK4a and p19ARF that restrain cell growth by modifying the functions of the retinoblastoma protein and p53, respectively. It is among the most frequently mutated tumor suppressor loci in human cancer. Both p16INK4a and p19ARF act as cell proliferation inhibitors. The ARF gene, p19ARF in mouse and p14ARF in human, has become an important player in cell cycle regulation. In mice, tumor suppressor effects appear to be mediated by interactions between p19ARF and the p53 tumor suppressor protein. p19ARF counters uncontrolled proliferation and oncogenic signals in p53 dependent pathways. Both p16INK4a and p19ARF are expressed in many cells as they emerge from the apoptotic crisis that characterizes the transformation process. Expression of p19ARF but not p16INK4a induces apoptosis in Ab-MLV-transformed pre-B cells.