We have previously disclosed several closely related series of cathepsin S inhibitors based upon a bicyclic pyrazole core structure. Although clear SAR trends were evident from examination of the enzymatic data of diverse structures, a comprehensive understanding of the mode of binding of these molecules to the target protein awaited structure determination via X-ray crystallographic analysis. In this presentation will be described the SAR of these inhibitors in the context of the key interactions observed in several co-crystal structures. The novel binding mode of these noncovalent cathepsin S will be compared to previously reported structures of inhibitors covalently-bound to cathepsin S, and the ramifications of these differences to drug design discussed.