Rearrangements of the MLL gene located at 11q23 are common chromosomal abnormalities associated with acute leukemia, especially infant and therapy-related leukemias. A variety of chimeric oncoproteins resulting from these rearrangements has been described; all of these include the NH(2)-terminal region of MLL implicated in protein-protein interactions and transcriptional repression. Although the molecular basis for the oncogenic activity of MLL chimeric proteins is incompletely understood, it seems to be derived, at least in part, through activation of clustered homeobox (HOX) genes. Here, we survey MLL gene rearrangements that are associated with acute leukemia and discuss molecular pathways leading to these rearrangements.