A series of dipeptidyl alpha-keto-beta-aldehydes (glyoxals), prepared by solid-/solution-phase chemistries, were assessed for their inhibitory activity against cathepsin S, a lysosomal cysteine protease implicated in a number of important pathophysiological processes. The inhibitor Cbz-Phe-Leu-COCHO, which exhibits slow-binding kinetic characteristics, was found to be almost 400-fold more selective for cathepsin S (K-i = 0.185 nM) than for cathepsin B (76 nM) and is, to our knowledge, the most potent, reversible, synthetic cathepsin S inhibitor reported to date.