It is now well appreciated that effective B cell antibody responses are essential for human health and protection against deadly infectious diseases and that on the flipside B cell antibodies are mediators of devastating autoimmune diseases and when released from normal control mechanisms B cell malignancies are common and many remain untreatable. It is also becoming increasingly clear that the mature B cell compartment is highly heterogeneous and that antigen-driven fates of individual B cells are dependent on a several factors including the affinity of the B cell antigen receptor (BCR) and how the BCR is wired to the B cell’s activation machinery as well as the quality of the immune environment defined by both antigen-specific T cells and innate immune cells responding to pathogen-derived signals. In this context the generation of long-lived protective immunity versus B cell malignancies or systemic autoimmunity may represent the spectrum of outcomes resulting from different combinations of BCR affinity and wiring and the T cell and innate signals experienced by B cells during activation. If so our ability to rationally manipulate B cell responses to develop vaccines against infectious diseases and therapies for autoimmune diseases and B cell cancers may be greatly accelerated by gaining a detailed understanding of the fundamentals of B cell biology and translating this knowledge to clinical and basic research addressing the most pressing public health priorities of our times in acute and chronic infectious diseases, autoimmunity and B cell malignancies.