The Set1 histone methyltransferase protein was first identified in yeast as part of the Set1/COMPASS histone methyltransferase complex, which methylates histone H3 on Lys4 and functions as a transcriptional co-ac-tivator. While yeast contain only one known Set1 protein, mammals contain six Set1-related proteins: SET1A, SET1B, MLL1, MLL2, MLL3 and MLL4, all of which methylate his-tone H3 on Lys4. These Set1-related proteins are each found in distinct protein complexes, all of which share the common structural subunits WDR5, RBBP5 and ASH2L. Like yeast Set1, all six Set1-related mammalian proteins methylate histone H3 on Lys4. MLL translocations are found in a large number of hematological malignancies, suggesting that Set1 histone methyltransferase complexes play a critical role in leukemogenesis.