Proteases are enzyme complexes that play a crucial role in the degradation of many proteins involved in regulation of cell cycle including G1, S and G2/M phases, apoptosis, cells growth and activation, adhesion, invasion, cell migration and metastasis, protein secretion, cellular interactions and signal transduction, phagocytosis and angiogenesis as well as tissue formation and stabilization. Thus, they show complete anticancer mechanisms. Proteases may be classified by their catalytic mechanisms into aspartic, serine, threonine, metallo- and cysteine proteases and are localized at the cellular surface or within specific sub cellular structures, in particular the lysosomes. In vitro and in vivo studies have reported the anticancer properties of protease inhibitors (PIs) but little is known about the clinical use of natural or chemical PIs, alone or in combination with other chemotherapies in humans. Thus, understanding the mechanisms of these drugs in prevention of cancer could result in them being used for treating the diseases. Furthermore, PIs can attenuate the drug toxicity in studies. They can also promote the defense mechanism, including induction of superoxide dismutase (SOD) and catalase (CAT) activity. These properties, on the one hand, suggest a wide spectrum of clinical applications for treatment and prevention of various cancers and on the other hand, further clinical and biological studies need to know the accordance mechanisms and discover new natural PIs. Thus, studying PIs will open a new anticancer strategy in treatment of various cancers in future.