Upon encounter with antigen, B lymphocytes differentiate into Ig-secreting plasma cells. This step involves a massive development of secretory organelles, most notably the endoplasmic reticulum. To analyze the relationship between organelle reshaping and Ig secretion, we performed a dynamic proteomics study of B lymphoma cells undergoing in vitro terminal differentiation. By clustering proteins according to temporal expression patterns, it appeared that B cells anticipate their secretory role in a multistep process. Metabolic capacity and secretory machinery expand first to accommodate the mass production of IgM that follows.