Errors that arise during DNA replication are corrected by the mismatch repair pathway (MMR), which detects base–base mismatches and insertion–deletion loops primarily via MutSα (comprising MutS homologue 2 (MSH2) and MSH6). Previous work had indicated that additional factors to the core MMR machinery, such as histone modifications, are needed for MMR in vivo. So Li et al. hypothesized that the MSH6 Pro-Trp-Trp-Pro (PWWP) domain, which acts as a 'reader' of trimethylated Lys36 on histone 3 (H3K36me3), is involved in this process. They found that MutSα preferentially binds to H3K36me3 in vitro and that the PWWP domain is essential for this. Moreover, H3K36me3 was shown to recruit MutSα to chromatin in vivo in G1 and early S phase, which might ensure that MutSα is present when DNA replication errors occur. Importantly, cells lacking H3K36me3 had an increased rate of spontaneous mutations and microsatellite instability (a hallmark of MMR). Therefore, H3K36me3 is involved in MMR by promoting the recruitment of MutSα to chromatin.