A wide array of recurrent, non-random chromosomal translocations are associated with hematologic malignancies; experimental models have clearly demonstrated that many of these translocations are causal events during malignant transformation. Translocations involving the MLL gene are among the most common of these non-random translocations. Leukemias with MLL translocations have been the topic of intense interest because of the unusual, biphenotypic immunophenotype of these leukemias, because of the unique clinical presentation of some MLL translocations (infant leukemia and therapy-related leukemia), and because of the large number of different chromosomal loci that partner with MLL in these translocations. This review is focused on the potential mechanisms that lead to MLL translocations, and will discuss aberrant VDJ recombination, Alu-mediated recombination, non-homologous end joining, as well as the effect of DNA topoisomerase II poisons and chromatin structure.