grp78/grp94 induction is critical for maintaining the viability of epithelial cells and fibroblasts following treatment with thapsigargin (TG), an inhibitor of Ca2+ uptake into the endoplasmic reticulum. In contrast to these cell types, WEHI7.2 mouse lymphoma cells undergo apoptosis when treated with TG, prompting us to examine the grp78/grp94 stress response in WEHI7.2 cells. TG treatment failed to induce grp78/grp94 transcription in WEHI7.2 cells, measured by Northern hybridization and nuclear run-on assays, even if the cells were protected from apoptosis by overexpressing bcl-2. However, grp78/grp94 transcription was induced by the glycosylation inhibitor tunicamycin, suggesting that there are at least two grp78/grp94 signaling pathways, one in response to TG-induced endoplasmic reticulum Ca2+ pool depletion, which is inoperable in WEHI7.2 cells, and one in response to glycosylation inhibition, which is operable in WEHI7.2 cells. Studies of additional lymphoid lines, as well as several nonlymphoid lines, suggested a correlation between grp78/grp94 induction and resistance to apoptosis following TG treatment. In conclusion, the vulnerability of TG-treated WEHI7.2 cells to apoptosis may be due to failure to signal a grp78/grp94 stress response.