The generation of B-lymphocytes from hematopoietic stem cells is controlled by multiple transcription factors regulating distinct developmental aspects. Ikaros and PU.1 act in parallel pathways to control the development of lymphoid progenitors in part by regulating the expression of essential signaling receptors (Flt3, c-Kit, and IL-7Rα). The generation of the earliest B cell progenitors depends on E2A and EBF, which coordinately activate the B cell gene expression program and immunoglobulin heavy-chain gene rearrangements at the onset of B-lymphopoiesis. Pax5 restricts the developmental options of lymphoid progenitors to the B cell lineage by repressing the transcription of lineage-inappropriate genes and simultaneously activating the expression of B-lymphoid signaling molecules. LEF1 and Sox4 contribute to the survival and proliferation of pro-B cells in response to extracellular signals. Finally, IRF4 and IRF8 together control the termination of pre-B cell receptor signaling and thus promote differentiation to small pre-B cells undergoing light-chain gene rearrangements.