Lymphocytes are derived from hematopoietic stem cells (HSC) following a series of regulated differentiation events. Multipotent HSCs become committed to the B cell lineage in bone marrow and the T cell lineage in the thymus after receiving appropriate signals from the corresponding microenvironment. These committed lymphoid cells must then undergo V(D)J recombination at the immunoglobulin gene or T cell receptor gene locus resulting in clonal production of functional B or T lymphocytes, respectively. Lymphocyte commitment and differentiation are accompanied by programmed gene expression or repression events which are driven by lineage and stage specific transcription factors. The basic-helix-loop-helix (bHLH) transcription factors encoded by the E2A gene are involved in several differentiation events during B and T cell development, including lineage commitment, initiation of V(D)J recombination, and antigen receptor mediated proliferation and differentiation. Several recent reviews have provided a comprehensive discussion of biochemical, cellular, and genetic research on E2A function in lymphocyte development (1,2). Here, we only discuss some of the genetic approaches our laboratory (except where it is noted) has undertaken to investigate the molecular pathways mediated by E2A transcription factors in lymphocyte development.