The application of various molecular modeling techniques has been recently reported in the design of several new cysteine protease inhibitors. Computational chemistry techniques have been used to understand and predict enzyme-inhibitor interactions and also to study enzyme mechanism and inhibitor reactivity. This review focuses on examples that use structure-based design or reflect cysteine proteases as a target class. In several cases X-ray crystallography and molecular modeling have significantly facilitated the inhibitor design process. Cysteine proteases can present extra challenges in molecular modeling, due to the covalent binding modes and the reactive nature of many of the inhibitors. We also discuss some of the key challenges in developing new tools to evaluate these properties and help in making informed decisions about new templates and leads.