Proteasomes are multi-subunit protein complexes, which present numerous targets for therapeutic interference. The most commonly used proteasome is 26S proteasome, which contains one 20S proteolytic core subunit and two 19S regulatory cap subunits. There are three different types of active sites of 20S proteolytic core and both, natural and synthetic proteasome inhibitors have been developed for this active site. The bortezomib is a Peptide boronate proteasome inhibitor and it targets the vital degradation process of intracellular protein, through proteasome. It is used for the treatment of non-Hodgkin lymphoma (NHL), mantle cell lymphoma, and multiple myeloma. There are newly developed Merizomib, Carfilzomib, ONX- 0912, TMC-95A, and Syringolin A proteasome inhibitors, which are being evaluated in clinical trials for the treatment of lymphoma and other cancers. The mechanisms of proteasome inhibitors are very typical because they affect various pathways, which are not completely understood. The mechanism of action of bortezomib is distinct from the other proteasome inhibitors, which are used in NHL treatments. There are various preclinical evidences, which indicate that the proteasome inhibitors have additive or synergistic property, with a bulk quantity of agents, either in vivo or in vitro, from cytotoxic to biological, which support an increasing quantity of combination studies, recently in progress in NHL patients.