Human leukemia with chromosomal band 11q23 aberrations that disrupt the MLL/HRX/ALL-1 gene portends poor prognosis1-13. MLL associated leukemias account for the majority of infant leukemia, ~10% of adult de novo leukemia, and ~33% of therapy related acute leukemia with balanced chromosome translocation. The 500kD MLL precursor is processed by Taspase1 to generate mature MLLN320/C180 which orchestrates many aspects of biology such as embryogenesis, cell cycle, cell fate, and stem cell. Leukemogenic MLL translocations fuse the common MLL N-terminus (~1,400 aa) in frame with more than 60 translocation partner genes (TPGs). Recent studies on MLL and MLL leukemia have greatly advanced our knowledge concerning the normal function of MLL and its deregulation in leukemogenesis. Here, we summarize the critical biological and pathological activities of MLL and MLL fusions, and discuss available models and potential therapeutic targets of MLL associated leukemias.