Summary: Plasma cells have long been recognized as the basis of humoral immunity, yet we are only now beginning to appreciate the complexities of plasma cell development and the fact that not all plasma cells are created equal. In vivo, plasma cells can arise from two developmental routes: one occurring outside the follicle and another within the germinal center. A B cell’s decision to follow one of these pathways is in part determined by the phenotypic subset to which it belongs and is also influenced by the nature of the antigen eliciting the response and the affinity of the B-cell receptor for that antigen. Once a plasma cell has chosen one of these pathways, the outcome of differentiation is relatively hard-wired. However, the phenotype of the plasma cells arising from these two pathways is distinct in terms of survival, location, and the quantity and quality of antibody they secrete. The extra-follicular pathway represents a relatively unchecked route to differentiation resulting in the generation of short-lived plasma cells that secrete low-affinity antibody. The germinal center response, however, allows the integration of external signals to delay plasma cell differentiation, eventually generating a plasma cell that secretes high-affinity antibody of an appropriate class, and that persists for a lifetime. The means by which these varying properties are conferred to a developing plasma cell are the subject of intense investigation.