The MLL gene, located at chromosome 11, band q23, is frequently disrupted by a variety of chromosomal rearrangements that occur in acute lymphoblastic leukemias and in a subset of de novo and secondary acute myeloid leukemias. In both scenarios, MLL rearrangements are associated with distinct clinical features and a poor prognosis. MLL encodes a large protein (MLL) that shares homology with the Drosophila trithorax protein. 11q23 translocations result in the generation of a series of acute leukemia-specific chimeric proteins that contain the N-terminus of MLL and are thought to be crucial to leukemogenesis. In this article, we review the structural features of the MLL fusion proteins as well as the clinical features and molecular diagnosis of acute leukemias containing MLL arrangements.