Proteasome inhibition has a validated role in cancer therapy since the successful introduction of bortezomib for the treatment of multiple myeloma (MM) and mantle cell lymphoma, leading to the development of second-generation proteasome inhibitors (PI) for MM patients in whom currently approved therapies have failed. Five PIs have reached clinical evaluation, with the goals of improving efficacy and limiting toxicity, including peripheral neuropathy (PN). Carfilzomib, an epoxyketone with specific chymothrypsin-like activity, acts as an irreversible inhibitor and was recently FDA approved for the response benefit seen in relapsed and refractory MM patients previously treated with bortezomib, thalidomide and lenalidomide. ONX-0912 is now under evaluation as an oral form with similar activity. The boronate peptides MLN9708 and CEP-18770 are orally bioactive bortezomib analogs with prolonged activity and greater tissue penetration. NPI-0052 (marizomib) is a unique, beta-lactone non-selective PI that has been shown to potently overcome bortezomib resistance in vitro. All of these second-generation PIs demonstrate encouraging anti-MM activity and appear to reduce the incidence of PN, with clinical trials ongoing.