The problem of HIV-1 drug resistance has established a need for new compounds that retain activity against mutated resistant viral isolates. Fortunately, a number of new compounds have recently been developed that possess excellent activity against HIV-1 strains that contain as many as eight relevant drug-resistance mutations in the viral protease (PR) gene. These newer protease inhibitors (PI) are characterized by higher genetic barrier for drug resistance, meaning that higher numbers of mutations are required for resistance to develop in comparison with older members of the PI family of drugs. Thus, different PIs can be used sequentially in HIV therapy in a manner that can overcome previous drug resistance and potentially forestall the development of additional resistance mutations in the viral PR. All currently used PIs, in general, require ritonavir to be used as a pharmacological boosting agent. There is a need to develop novel PIs, that will not require such boosting, and that are also characterized by potent antiviral activity and a high genetic barrier for resistance.