The 26S proteasome complex engages in an ATP-dependent proteolytic degradation 
of a variety of oncoproteins, transcription factors, cell cycle specific 
cyclins, cyclin-dependent kinase inhibitors, ornithine decarboxylase, and other 
key regulatory cellular proteins. Thus, the proteasome regulates either directly 
or indirectly many important cellular processes. Altered regulation of these 
cellular events is linked to the development of cancer. Therefore, the 
proteasome has become an attractive target for the treatment of numerous 
cancers. Several proteasome inhibitors that target the proteolytic active sites 
of the 26S proteasome complex have been developed and tested for anti-tumor 
activities. These proteasome inhibitors have displayed impressive anti-tumor 
functions by inducing apoptosis in different tumor types. Further, the 
proteasome inhibitors have been shown to induce cell cycle arrest, and inhibit 
angiogenesis, cell-cell adhesion, cell migration, immune and inflammatory 
responses, and DNA repair response. A number of proteasome inhibitors are now in 
clinical trials to treat multiple myeloma and solid tumors. Many other 
proteasome inhibitors with different efficiencies are being developed and tested 
for anti-tumor activities. Several proteasome inhibitors currently in clinical 
trials have shown significantly improved anti-tumor activities when combined 
with other drugs such as histone deacetylase (HDAC) inhibitors, Akt (protein 
kinase B) inhibitors, DNA damaging agents, Hsp90 (heat shock protein 90) 
inhibitors, and lenalidomide. The proteasome inhibitor bortezomib is now in the 
clinic to treat multiple myeloma and mantle cell lymphoma. Here, we discuss the 
26S proteasome complex in carcinogenesis and different proteasome inhibitors 
with their potential therapeutic applications in treatment of numerous cancers.