Recurrent reciprocal chromosomal translocations are frequently found in leukaemias and sarcomas as initiating events in these cancers. Mouse models of chromosomal translocations are not only important for the elucidation of the mechanism of these factors underlying the disease but are also important pre-clinical models for assessing new drug combinations, developing new rational therapeutic strategies based on new drugs and testing novel macromolecular drugs. We describe three technologies for creating chromosomal translocation mimics in mice, applied specifically to understand how the MLL-fusions contribute to leukaemia. An important finding of this work is that the lineage of the tumours can be controlled by the MLL-protein fusion. The translocation mimic methods can be applied to any human reciprocal chromosomal translocation.