The INK4b–ARF–INK4a locus encodes two members of the INK4 family of cyclin-dependent kinase inhibitors, p15 INK4b and p16 INK4a, and a completely unrelated protein, known as ARF. All three products participate in major tumour suppressor networks that are disabled in human cancer and influence key physiological processes such as replicative senescence, apoptosis and stem-cell self-renewal. Transcription from the locus is therefore kept under strict control. Mounting evidence suggests that although the individual genes can respond independently to positive and negative signals in different contexts, the entire locus might be coordinately suppressed by a cis-acting regulatory domain or by the action of Polycomb group repressor complexes.