HCV NS3, a serine protease, that when bound to NS-4A cofactor facilitates development of mature virons by catalyzing cleavage of a single polyprotein to form functional and structural proteins of HCV. X-ray structure of the enzyme reveal a very shallow binding pocket at the catalytic site which makes development of inhibitors a daunting task. Various novel approaches have been used to design, preorganized, depeptidized macrocyclic inhibitors linking the P(2)-P(4) residues and P(1)-P(3) groups. The design and structure activity relationship of these macrocyclic inhibitors are reviewed in the following article. X-ray structure of inhibitor bound to the active site of the enzyme is also discussed. Macrocyclization proved to be an effective tool for depeptidization of peptidic inhibitors, imparting enhanced metabolic stability and improved pharmacokinetic properties in the resultant molecules.