B cells are an integral part of the adaptive immune system and regulate innate immunity. Derived from hematopoietic stem cells, B cells mature through a series of cell fate decisions. Complex transcriptional circuits form and dissipate dynamically during these lineage restrictions. Genomic aberrations of involved transcription factors underlie various B-cell disorders. Acquired somatic aberrations are associated with cancer, whereas germline variations predispose to both malignant and nonmalignant diseases. We review the opposing role of transcription factors during B-cell development in health and disease. We focus on early B-cell leukemia and discuss novel causative gene–environment cooperation and their implications for precision medicine. Childhood leukemia is frequently initiated during fetal hematopoiesis. Clinical silent preleukemic clones are detectable in cord blood of a large number of healthy newborns. These predisposing alterations cooperate with environmental factors to trigger leukemia onset. Understanding of the underlying principles is a prerequisite for the development of measures to prevent leukemia in children.