The gene E2A on chromosome 19 is involved in recurrent chromosomal rearrangements associated with pediatric acute lymphoblastic leukemia. The resulting fusion of 5' E2A sequences with 3' portions of other genes leads to the expression of two well-characterized fusion proteins: E2A-PBX1 and E2A-HLF. Since the E2A, PBX1 and HLF proteins all appear to function as transcription factors, it appears likely that the oncogenic fusion proteins contribute to leukemia development by causing abnormal transcriptional regulation of key target genes. Furthermore, since the E2A portion of the fusion proteins contains transcriptional activation domains, and the PBX1 and HLF portions contain DNA binding domains, leukemogenesis may be due, at least in part, to excessive transcriptional induction of target genes defined by PBX1 or HLF. However, recent findings suggest that this model is simplistic and possibly incorrect. In this article, I review the evidence pertaining to leukemogenesis by the well-characterized E2A-fusion proteins and consider its mechanistic implications.