As myeloma cells actively produce and secrete immunoglobulins, they are prone to ER stress, which if unresolved leads to apoptosis. We found that myeloma cell death induced by the ER stressor Thapsi-gargin was highly variable, ranging from 2 to 89%. Induction of ATF4 and CHOP was observed in myeloma cells under Thapsigargin independently of cell death. The decrease in Mcl-1 was associated with protein translation inhibition and identified as a crucial factor in Thapsigargin sensitivity, since it was the only Bcl-2 family protein differentially modified between sensitive and resistant myeloma cells. Bak but not Bax was found to contribute to Thapsigargin-induced apoptosis. Appropriately, a basal Mcl-1/Bak interaction was demonstrated in Thapsigargin-sensitive cells. Of note, the only pro-apoptotic protein freed from Mcl-1 under Thapsigargin was Bak, whereas Mcl-1/Noxa or Mcl-1/Bim complexes were simultaneously increased. Thus, the disruption of the basal Mcl-1/Bak complex in Thapsigargin-sensitive cells seemed to be an essential event in cell death induction, probably favored by the induced Noxa and Bim BH3-only proteins. These findings underscore the implication of the Mcl-1/Bak axis in myeloma cell death triggered by Thapsigargin.