A significant number of the malignancies of the immune system are the result of nonrandom chromosomal translocations that cause either the overexpression of endogenous genes or the production of novel chimeric factors that can promote uncontrolled cell growth and block differentiation. Translocations which fuse the gene encoding the basic helix±loop±helix transcription factor E2A with either the gene encoding the homeodomain protein PBX1 or the bZIP protein HLF result in the generation of chimeric proteins that can cause pre-and pro-B cell acute lymphoblastic leukemias (ALL), respectively. What is currently known about the E2A-HLF fusion protein is reviewed elsewhere in this issue. This review focuses on the mechanisms and models of E2A-PBX1-mediated pre-B cell transformation.