A hallmark of thymus-dependent immunity is the generation of long-lived humoral immune responses. The production of long-lived memory B cells (B(mem)) and plasma cells (PCs) form the cellular basis for sustaining antibody-mediated immunity. During an immune response, the differentiation of B cells to become a B(mem) or PC occurs largely at the level of single cell fate decisions. Both of these cell populations acquire longevity as a result of antigen-specific, CD40-dependent, cognate interactions with helper T cells within germinal centers (GCs). In addition to these cellular elements that sustain humoral immunity, a novel GC-derived B cell that is a precursor to PCs has also been described. This cell is long-lived, highly proliferative, and terminally differentiates to end-stage cells within the bone marrow, and represents yet another cellular element that contributes to the long-lived nature of humoral immunity. Recent studies have shown that abnormalities in the B cell compartment of patients and mice with antibody-mediated autoimmune disease results from spontaneous GC responses, leading to the dysregulation in the development of PCs that produce pathogenic autoantibodies with altered homeostasis. The underlying cellular and molecular events that drive the loss of self-tolerance remain poorly understood. However, newer studies demonstrate that the strength of signaling via the B cell receptor, CD40 and BAFF receptors controls B cell fate decisions. Alterations in the magnitude of signaling through these molecules likely contribute to immune dysregulation that leads to the loss of self-tolerance. Understanding the processes of normal PC differentiation will provide strategic insights into identifying therapeutic targets for the treatment of antibody-mediated autoimmunity.