Cancer is the second cause of death in 2015, and it has been estimated to surpass heart diseases as the leading cause of death in the next few years. Several mechanisms are involved in cancer pathogenesis. Studies have indicated that proteases are also implicated in tumor growth and progression which is highly dependent on nutrient and oxygen supply. On the other hand, protease inhibitors could be considered as a potent strategy in cancer therapy. On the basis of the type of the key amino acid in the active site of the protease and the mechanism of peptide bond cleavage, proteases can be classified into six groups: cysteine, serine, threonine, glutamic acid, aspartate proteases, as well as matrix metalloproteases. In this review, we focus on the role of different types of proteases and protease inhibitors in cancer pathogenesis.