Proteases are essential enzymes which regulate physiological processes such as inflammation, infection, fertilization, allergic reactions, cell growth and death, blood clotting, tumor growth and bone remodeling. The protease family consists of six major classes of enzymes which are aspartic-, serine-, cysteine-, threonine-, glutamic-, and metalloproteases, all which are implicated in disease propagation. Therefore, protease inhibitors have been of great interest as possible targets for the development of novel therapies. Although, many protease inhibitors have followed a structural design based on either a peptidic or peptidomimetic backbone, other chemical scaffolds have recently emerged. Utilizing structure- and fragment-based design guided by X-ray crystallography, NMR spectroscopy, computational and/or extended tethering approaches, potential non-peptidic therapeutic agents could be identified. In this review, we will report on the recent developments of nonpeptidic cysteine- and metallo- protease inhibitors, focusing on their design by using such strategies.