The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)-cyclin protein complex(1). However, control of the G0-to-G1 transition is not completely understood. Here we demonstrate that p38 MAPK gamma (p38 gamma) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycle. p38 gamma shares high sequence homology, inhibition sensitivity and substrate specificity with CDK family members. In mouse hepatocytes, p38 gamma induces proliferation after partial hepatectomy by promoting the phosphorylation of retinoblastoma tumour suppressor protein at known CDK target residues. Lack of p38 gamma or treatment with the p38 gamma inhibitor pirfenidone protects against the chemically induced formation of liver tumours. Furthermore, biopsies of human hepatocellular carcinoma show high expression of p38 gamma, suggesting that p38 gamma could be a therapeutic target in the treatment of this disease.