The present invention relates to prodrugs of protease inhibitors, such as inhibitors of the proteosome, DPP IV, FAPα 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 as pro-inhibitors being referred 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-inactivate by, e.g., intramolecular-cyclization or cis-trans isomerization.