Inactivation of mismatch repair (MMR) complexes causes susceptibility to certain cancers and a cellular mutator phenotype characterized by microsatellite instability and increased frequency of spontaneous mutation. However, not all cancers with a mutator phenotype have defects in MMR machinery. Now, Liya Gu, Guo-Min Li and colleagues report a new regulator of MMR, shedding light on how seemingly MMR-proficient tumors can have a mutator phenotype (Cell 153, 590–600, 2013). The authors show that the DNA mismatch repair protein hMSH6 interacts with histone H3 trimethylated at lysine 36 (H3K36me3) and that H3K36me3 recruits hMSH6 to chromatin. They also show that the H3K36 methyltransferase SETD2 is required for DNA mismatch repair, as loss of SETD2 causes a mutator phenotype with microsatellite instability and increased rates of spontaneous mutation. They further show that tumor cell lines with loss of SETD2 have loss of H3K36me3 marks, loss of hMSH6 recruitment to chromatin and a mutator phenotype. This work suggests a molecular mechanism to explain SETD2 tumorigenic driver mutations.