The mixed-lineage leukemia (MLL) gene is a trithorax group (trxG) gene that was originally identified at chromosomal translocations in patients developing acute leukemia. Although Polycomb group (PcG) genes, which counteract trxG genes, were found to play essential roles in hematopoiesis, little has been understood about the roles of trxG genes in hematopoiesis except for MLL. MLL has been found fused with 1 of more than 30 different partner genes to yield a diverse collection of MLL fusion oncoproteins that lead to the aberrant expression of HOX genes. Recent studies have revealed that MLL assembles, as do some trxG proteins, into a chromatin-modifying transcriptional regulatory supercomplex to regulate epigenetic pathways, including the methylation of histone H3 lysine 4, which is conferred by the Su (var)3-9, enhancer of zeste, and tritho-rax (SET) domain. Other studies also indicated that MLL plays a nonredundant and essential role in definitive hematopoiesis and induces the proliferation and differentiation of hematopoietic progenitors by maintaining appropriate up-regulation of HOX genes. Further progress in the field will provide novel insights into trxG- and PcG-mediated hematopoiesis and help us understand the epigenetic process by which developing stem cells coordinate proliferation and differentiation.