The transition of a mature B cell into an antibody-secreting cell involves an increase in cell size and an increase in the cell's secretory capacity. Homeostasis of the endoplasmic reticulum under pharmacologic conditions which "stress" its capacity is maintained through activation of an intracellular signaling pathway known as the Unfolded Protein Response (UPR). Here, the role of the UPR in a physiological situation, the differentiation of resting B lymphocytes into antibody-secreting cells, was investigated. In contrast to the standard UPR which activates all three branches of the UPR pathway (IRE-1, ATF6, and PERK), only components of the IRE-1 and ATF-6 branches were detectably activated in B cells differentiating in response to LPS. Some, but not all, components of the PERK branch of the UPR were detected in differentiating B cells. Using B cells from Perk^-/- mice, it was determined that PERK is not required either for B cell development or for B differentiation to an antibody-secreting cell. Moreover, modulation of new protein synthesis during the course of LPS stimulation was observed in both wild-type and Perk^-/-B cells. Therefore, differentiating B cells may utilize an alternative method of regulating protein synthesis. The lack of activation of the PERK pathway during the differentiation process may be due to the presence of an inhibitory factor induced in B cells or by differences in the activation threshold of UPR sensors. These studies provide new insight into mechanisms that influence the development and function of antibody-secreting plasma cells. Furthermore, the data contribute to the emerging evidence that the physiologic UPR is variable among cell types and developmental processes, apparently tailored according to the specific needs of the secretory pathway in different situations.