B lymphocytes are essential antibody‐producing cells of the immune system. During the development of progenitor B cells to mature B cells that express a membrane‐bound antibody, the B cell receptor (BCR), the cells undergo selection at several checkpoints, which ensures that a diverse antibody repertoire is generated and that the BCRs recognise foreign‐, but not self‐, antigens. In this review, we consider the pre‐BCR checkpoint. Mutations or alterations that affect this checkpoint underpin the development of pre‐B cell leukemias, primary immunodeficiency, and possibly, systemic autoimmunity.