Humoral immunity following vaccination or infection is mainly derived from two types of cells: memory B cells and plasma cells. Memory B cells do not actively secrete antibody but instead maintain their immunoglobulin in the membrane‐bound form that serves as the antigen‐specific B‐cell receptor. In contrast, plasma cells are terminally differentiated cells that no longer express surface‐bound immunoglobulin but continuously secrete antibody without requiring further antigenic stimulation. Pre‐existing serum or mucosal antibody elicited by plasma cells (or other intermediate antibody‐secreting cells) represents the first line of defense against reinfection and is critical for protection against many microbial diseases. However, the mechanisms involved with maintaining long‐term antibody production are not fully understood. Here, we examine several models of long‐term humoral immunity and present a new model, described as the ‘Imprinted Lifespan’ model of plasma cell longevity. The foundation of this model is that plasma cells are imprinted with a predetermined lifespan based on the magnitude of B‐cell signaling that occurs during the induction of an antigen‐specific humoral immune response. This represents a testable hypothesis and may explain why some antigen‐specific antibody responses fade over time whereas others are maintained essentially for life.