B lymphocytes are small cells that express antigen receptors and secrete little if any IgM. Upon encounter with antigen, they differentiate into short-lived plasma cells, which secrete large amounts of polymeric IgM. Plasma cell differentiation entails a massive development of the endoplasmic reticulum to sustain high levels of Ig production. Recent findings suggest a role for the unfolded protein response in orchestrating the architectural and functional changes during terminal plasma cell differentiation.