The two products of the Ink4a–Arf locus, p16^Ink4a and p19^Arf (p14^ARF in humans), are potent tumor suppressors that regulate the activities of the retinoblastoma protein and the p53 transcription factor. These proteins form part of a signaling network that is disrupted in most, if not all, cancer cells. The Ink4a-Arf locus responds to stress signals, limiting cell proliferation and modulating oncogene-induced apoptosis. Recent evidence emerging from mouse tumor models distinguishes the activities of p16^Ink4a and p19^Arf in regulating tumor onset and identifies differences in their responsiveness to drugs.