With the approval by the U.S. Food and Drug Administration of bortezomib for the treatment of multiple myeloma and mantle cell lymphoma, the proteasome was clinically validated as a target in oncology. The proteasome is part of a complex cellular pathway that controls the specificity and rate of degradation of the majority of proteins in the cell. The search for additional drug targets in the proteasomal pathway is ongoing. In parallel, the next generation of proteasome inhibitors, exhibiting some properties distinct from that of bortezomib, are currently being studied in clinical trials. The key question will be whether these distinctions can improve upon the clinical efficacy and safety standards established by bortezomib and refine our understanding of the mechanism by which proteasome inhibitors are effective in the treatment of cancer. Clin Cancer Res; 18(1); 15–20. ©2011 AACR.