In this review we summarize recent insights into the development of human B cells primarily by studying immunodeficiencies. Development and differentiation of B cells can be considered as a paradigm for many other developmental processes in cell biology. However, it differs from the development of many other cell types by phases of extremely rapid cell division and by defined series of somatic recombination and mutation events required to assemble and refine the B cell antigen receptors. Both somatic DNA alteration and proliferation phases take place in defined sites but in different organs. Thus, cell migration and timely arrival at defined sites are additional features of B cell development. By comparing experimental mouse models with insights gained from studying defined genetic defects leading to primary immunodeficiencies and hypogammaglobulinemia, we address important features that are characteristic for human B cells. We also summarize recent advances made by developing improved in vitro and in vivo systems allowing the development of human B cells from hematopoietic stem cells. Combined with genetic and functional studies of immunodeficiencies, these models will contribute not only to a better understanding of disease affecting the B lymphocyte compartment, but also to designing better and safer novel B cell-targeted therapies in autoimmunity and allergy.