0 VER THE PAST DECADE, significant advances have been made in understanding the molecular details of lymphopoiesis and the pathogenesis of lymphoid neoplasia. Major contributions to these advances have been made through study of Ifl-cell receptor (TCR) genes and the factors that control their ordered recombination and by investigation of nonrandom chromosomal translocations that occur in acute lymphoblastic leukemia (ALL). In addition, the advent of technology that allows investigators to genetically inactivate or “knockout” individual genes by creating homozygous null mice has facilitated efforts to identify proteins whose function is essential for normal development. These disparate lines of investigation have shown that the protein products of the E2A gene are essential for normal lymphopoiesis and can be converted into oncogenic tran-scription factors by chromosomal translocations. In this review, I will summarize briefly our current understanding of the function of E2A proteins within the lymphoid system, particularly genetic evidence showing that they are absolutely required for normal B-cell development. Attention will then be turned to discussing two translocations, t (1; 19)(q23; p13) and t (17; 19)(421-22;~ 13), that disrupt E2A. The clinical features of t (1; 19)’and t (17; 19)+ ALLs will be reviewed, particularly those of the former that illustrate the clinical importance of molecular diagnosis. I will also discuss, in detail, the structural features and functional properties of E2A-PBX1 and E2A-HLF, the fusion proteins created by the t (1; 19) and t (17; 19), respectively, and will review the experimental evidence implicating these chimeras in leukemogenesis.