A key feature of multiple myeloma is the buildup of immunoglobulin-secreting plasma cells in the bone marrow. To accommodate the synthesis of secretory immunoglobulin, the endoplasmic reticulum (ER) of these cells expands, and it is thought that proteasome inhibitors hinder ER function by blocking proteasome-assisted, ER-associated degradation. Now, Rodger Tiedemann and colleagues report a new mechanism of intrinsic proteasome inhibitor resistance in multiple myeloma (Cancer Cell 24, 289–304, 2013). In reanalyzing genome-wide small interfering RNA (siRNA) screening data, the authors noticed that the gene IRE1 was required for proteasome inhibitor–induced cell death in a multiple myeloma cell line. Silencing of IRE1 led to proteasome inhibitor resistance in six other multiple myeloma cell lines. Ire1 signaling is mediated via the transcription factor Xbp1, and analysis of gene expression in tumor samples pretreated with proteasome inhibitor showed that all Xbp1 target genes had lower expression in multiple myeloma tumors that subsequently appeared refractory to proteasome inhibitor treatment. The authors purified plasma cell progenitor populations present in multiple myeloma tumors and found that such cells were negative for Xbp1s. The authors conclude that such Xbp1s-negative plasma cell progenitors are intrinsically insensitive to proteasome inhibitor, which may account for failures in treating multiple myeloma with proteasome inhibitor.