Trimethylation of histone H3 Lys4 (H3K4) is associated with transcriptional activation. One of the chief effectors of H3K4 methylation is mixed-lineage leukemia 1 (MLL1), a gene that is disrupted by chromosomal translocation in acute leukemia and a master regulator of Hox and other genes. In a recent paper, core components of the human MLL histone methyltransferase (MT) complex were found to form a structural platform, with one component (WDR5) mediating association between the specific histone H3K4 substrate and the MT. This novel regulatory mechanism, which is conserved from yeast to human, is required for both methylation and downstream target gene transcription.