The p16^INK4a cyclin-dependent kinase inhibitor is implicated in replicative senescence, the state of permanent growth arrest provoked by cumulative cell divisions or as a response to constitutive Ras–Raf–MEK signalling in somatic cells^,,,,,,. Some contribution to senescence presumably underlies the importance of p16^INK4a as a tumour suppressor but the mechanisms regulating its expression in these different contexts remain unknown. Here we demonstrate a role for the Ets1 and Ets2 transcription factors based on their ability to activate the p16^INK4a promoter through an ETS-binding site and their patterns of expression during the lifespan of human diploid fibroblasts. The induction of p16^INK4a by Ets2, which is abundant in young human diploid fibroblasts, is potentiated by signalling through the Ras–Raf–MEK kinase cascade and inhibited by a direct interaction with the helix–loop–helix protein Id1 (ref. ). In senescent cells, where the Ets2 levels and MEK signalling decline, the marked increase in p16^INK4a expression is consistent with the reciprocal reduction of Id1 and accumulation of Ets1.