CDK8 is a dissociable kinase module of the Mediator complex and has been shown to play an important role in transcriptional regulation in organisms as diverse as yeast and humans. Recent studies suggest that CDK8 functions as an oncoprotein in melanoma and colon cancer. Importantly, these studies were conducted usingin vitrocell line models and the role of CDK8 in tumourigenesisin vivohas not been explored. We have generated a mouse with aCdk8 conditional knockout allele and examined the consequences ofCdk8 loss on normal tissue homeostasis and tumour developmentin vivo. Cdk8 deletion in the young adult mouse did not induce any gross or histopathological abnormalities, implying thatCdk8 is largely dispensable for somatic cellular homeostasis. In contrast,Cdk8 deletion in theApcMinintestinal tumour model shortened the animals' survival and increased tumour burden. AlthoughCdk8deletion did not affect tumour initiation, intestinal tumour size and growth rate were significantly increased inCdk8-null animals. Transcriptome analysis performed onCdk8-null intestinal cells revealed up-regulation of genes that are governed by the Polycomb group (PcG) complex. In support of these findings,Cdk8-null intestinal cells and tumours displayed a reduction in histone H3K27 trimethylation, both globally and at the promoters of a number of PcG-regulated genes involved in oncogenic signalling. Together, our findings uncover a tumour suppressor function for CDK8in vivoand suggest that the role of CDK8 activity in driving oncogenesis is context-specific. Sequencing data were deposited at GEO (Accession No. GSE71385). Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.