HIV-1 protease is an aspartic protease composed by two identical monomers, 99 amino acids in length. Drug resistance is mainly mediated by structural changes in the substrate cleft that result in a reduction in drug binding affinity. Sequence analysis of drug resistance clones has shown mutations not only within the protease but also at several of the protease cleavage sites. Changes at more than 20 positions within the HIV-1 genome have been associated with PI resistance. The spectrum of mutations selected during therapy with indinavir, nelfinavir, saquinavir, ritonavir, amprenavir and atazanavir has been well characterized. Specific changes are characteristically linked to resistance to each of these compounds (i.e., D30N for nelfinavir, I50L for atazanavir or I50V for amprenavir). In contrast, for drugs such as lopinavir and tipranavir, which always are used boosted with low-dose ritonavir, combinations of multiple protease mutations rather than few specific changes seem to be necessary for causing significant drug resistance. Something similar happens when other PIs are equally boosted with ritonavir. Overall, when more than 5 protease resistance mutations are present, the response to any boosted-PI should be expected to be compromised.