Efforts to understand and target the integrated ER stress response in myeloma will be summarized here, with a focus on the three ER stress sensors that coordinate this response: inositol requiring kinase 1 (IRE1; Sidrauski and Walter, 1997; Yoshida et al., 2001), double stranded RNA-activated protein kinase-like ER kinase (PERK; Harding et al., 2000), and the transcription factor activating transcription factor 6 (ATF6; Yoshida et al., 2000). Here, ATF6 is linked to plasma cell myeloma.