The protein p63 is crucial for the correct development of stratifying epithelia, and is a key regulator of epithelial cell proliferation and differentiation. In keratinocytes, deletion of all p63 isoforms results in hypoproliferation and loss of differentiation. The pathways through which this p53 family member maintains their proliferative capacity, however, are not well characterised. On page 1635, Dennis McCance and colleagues now identify the S-phase kinase associated protein 2 (Skp2) and the retinoblastoma (Rb) family member p130 as new components that regulate keratinocyte proliferation. The authors find that depletion of the α- and β-subunits of p63 by using RNA interference increases expression of the cyclin-dependent kinase inhibitor p21 in both a p53-dependent and a p53-independent manner. Because p21 inhibits the cell cycle through members of the Rb family, the researchers also investigate the effect of p21 upregulation on p130 – and show that p63 knockdown results in markedly increased levels of p130. Depleting the levels of p53, p21 or p130 in p63-deficient cells reverses the hypoproliferative phenotype. The authors further show that the lack of p63 results in a decrease in Skp2. On the basis of these findings they conclude that, in the absence of p63, a decrease in Skp2-dependent ubiquitylation and degradation of p53, p21 and p130 results in the loss of proliferative capacity.