The first general method has been developed for the expedient solid-phase synthesis of ketone-based cysteine protease inhibitors. The synthesis approach was designed to allow the introduction of diverse functionality at all variable sites about the ketone carbonyl using readily available precursors. The chloromethyl ketone scaffold 7 is attached to the solid support through the newly developed hydrazine linker 6. Successful nucleophilic displacement of the support-bound a-chloro hydrazones 8 with carboxylates, thiolates, and amines provides entry to the acyloxymethyl, mercaptomethyl, and amidomethyl ketone classes of cysteine protease inhibitors. Further transformations followed by cleavage from support provides the fully substituted ketone products in 40-100% overall yields after release from support. Significantly, racemization of the alpha-stereocenter does not occur during loading onto support, nucleophilic displacement, or cleavage from support.