More than three decades ago, genetic studies identified the Drosophila ash1 gene as a positive regulator of HOX genes, and Ash1 was therefore classified as a trithorax-group (trxG) protein. Subsequent investigations revealed that a key function of Ash1 at HOX genes is to counteract Polycomb-mediated repression, that Ash1 exhibits histone methyltransferase (HMTase) activity for dimethylating histone H3 at lysine 36 (H3K36me2) and that this modification antagonizes H3 methylation by Polycomb. But precisely how and where Ash1 acts remained unknown. Now, Jürg Müller and colleagues report the biochemical and functional characterization of Ash1 protein complexes. They show that Ash1 purified from Drosophila embryos exists in a complex with MRG15 and Caf1; the authors name this complex ‘AMC’. Biochemical reconstitution of AMC reveals that the interaction between MRG15 and Ash1 greatly stimulates Ash1 HMTase activity on nucleosomes. The authors further report that Drosophila MRG15 knockout and ash1 catalytic mutants exhibit the classic homeotic phenotypes characteristic of trxG mutants. They also show that H3K36me2 in AMC mutants is specifically reduced in the chromatin of HOX and other AMC-regulated genes. Together, these findings identify AMC as a novel trxG protein complex and reveal that H3K36me2 deposition at HOX genes is the mechanism by which this complex safeguards these genes from Polycomb-mediated repression.