Rapid advances in genomics have opened unprecedented possibilities to explore the mutational landscapes in malignant diseases, such as B-cell acute lymphoblastic leukemia (B-ALL). This disease is manifested as a severe defect in the production of normal blood cells due to the uncontrolled expansion of transformed B-lymphocyte progenitors in the bone marrow. Even though classical genetics identified translocations of transcription factor-coding genes in B-ALL, the extent of the targeting of regulatory networks in malignant transformation was not evident until the emergence of large-scale genomic analyses. There is now evidence that many B-ALL cases present with mutations in genes that encode transcription factors with critical roles in normal B-lymphocyte development. These include PAX5, IKZF1, EBF1, and TCF3, all of which are targeted by translocations or, more commonly, partial inactivation in cases of B-ALL. Even though there is support for the notion that germline polymorphisms in the PAX5 and IKZF1 genes predispose for B-ALL, the majority of leukemias present with somatic mutations in transcription factor-encoding genes. These genetic aberrations are often found in combination with mutations in genes that encode components of the pre-B-cell receptor or the IL-7/TSLP signaling pathways, all of which are important for early B-cell development. This review provides an overview of our current understanding of the molecular interplay that occurs between transcription factors and signaling events during normal and malignant B-lymphocyte development.