The present invention relates to prodrugs of protease inhibitors, such as inhibitors of proteosome, DPOP IV, FAP.alpha. and the like. These "pro-inhibitors" are activated, i.e., cleaved by an "activated protease" to release an active inhibitor moiety in proximity to a "target protease". The identity of activating protease and target protease can be the same (such pro-inhibitors being refered to as "Target-Activated Smart Protease Inhibitors" or "TASPI") or different (e.g., "Target-Directed Smart Protease Inhibitors" or "TDSPI"). After activation of the pro-inhibitor, the active inhibitor moiety can self-inactive by, e.g., intramolecular-cyclization or cis-trans isomerization.