Recurrent reciprocal chromosomal translocations are present in more than 50% of leukemias. A deeper understanding of how they affect cancer initiation is essential for evaluating the origins of cancer and the potential for therapy based on the translocation products. Mouse models of chromosomal translocations are required for this. Here we summarize three methodologies developed in our laboratory to model chromosomal translocations (knock-in, translocator, and invertor methods). We have used these models to study leukemias caused by fusions of the mixed lineage leukemia (MLL) gene and the Ews-ERG fusion gene to evaluate oncogenicity and elucidate some general principles about translocation products. We show that MLL fusions have the capacity to cause hematopoietic tumors only if expressed in permissive cells and that the Mll-Enl fusion can cause lineage reassignment if the chromosomal translocation occurs in lineage noncommitted progenitors. The leukemia-initiating cells generated by Mll fusions or by Ews-ERG fusion can be committed cells within the hematopoietic pathway. Our translocation mimic models are applicable to any human reciprocal chromosomal translocation.