Among other cellular processes, gene expression is regulated by epigenetic histone modifications. Histone methyltransferases catalyze the transfer of the methyl group from S-adenosylmethionine to specific lysine residues on histones. Mixed lineage leukemia 1 (MLL1) is a methyltransferase that methylates lysine 4 on histone H3 (H3K4me3) and is an important regulator of the haemopoietic system. Deregulation of MLL1 is often associated with acute myeloid and lymphoid leukemias and was proposed as a novel therapeutic target. WD40 repeat protein 5 (WDR5) is a component of the multiprotein MLL1 complex that is essential for its methyltransferase activity. Thus, therapeutic intervention of the WDR5/MLL1 interaction may lead to possible novel therapeutic agents for MLL-dependent leukemias. Using a structure-based design approach our structure activity relationship studies identified selective and cell-permeable compounds that bind to WDR5 with low nanomolar affinities. In future chemical biology studies these molecules will serve as valuable molecular probes to dissect the biological role of WDR5.