D-TYPE cyclins, in association with the cyclin-dependent kinases Cdk4 or Cdk6, promote progression through the Gl phase of the cell cycle^1–6 by phosphorylating the retinoblastoma protein (RB)^7,8. The activities of Cdk4 and Cdk6 are constrained by inhibitors^9–12 such as pi6, the product of the CDKN2 gene on human chromosome 9p21 (refs 12–14). The frequent deletion or mutation of CDKN2 in tumour cells suggests that pi6 acts as a tumour suppressor. We show that wild-type pi6 arrests normal diploid cells in late Gl, whereas a tumour-associated mutant of pi6 does not. Significantly, the ability of pi6 to induce cell-cycle arrest is lost in cells lacking functional RB, including primary fibroblasts from Rb_-/- mouse embryos. Thus, loss of pi6, overexpression of D-cyclins and loss of RB have similar effects on Gl progression, and may represent a common pathway to tumorigenesis.