The current effectiveness of HAART in the management of HIV infection is compromised by the emergence of extensively cross-resistant strains of HIV-1, requiring a significant need for new therapeutic agents. Due to its crucial role in viral maturation and therefore HIV-1 replication and infectivity, the HIV-1 protease continues to be a major development target for antiretroviral therapy. However, new protease inhibitors must have higher thresholds to the development of resistance and cross-resistance. Research has demonstrated that the binding characteristics between a protease inhibitor and the active site of the HIV-1 protease are key factors in the development of resistance. More specifically, the way in which a protease inhibitor fits within the substrate consensus volume, or “substrate envelope”, appears to be critical. The currently available inhibitors are not only smaller than the native substrates, but also have a different shape. This difference in shape underlies observed patterns of resistance because primary drug-resistant mutations often arise at positions in the protease where the inhibitors protrude beyond the substrate envelope but are still in contact with the enzyme. Since all currently available protease inhibitors occupy a similar space (in spite of their structural differences) in the active site of the enzyme, the specific positions where the inhibitors protrude and contact the enzyme correspond to the locations where most mutations occur that give rise to multidrug-resistant HIV-1 strains. Detailed investigation of the structure, thermodynamics, and dynamics of the active site of the protease enzyme is enabling the identification of new protease inhibitors that more closely fit within the substrate envelope and therefore decrease the risk of drug resistance developing. The features of darunavir, the latest FDA-approved protease inhibitor, include its high binding affinity (Kd = 4.5 × 10-12 M) for the protease active site, the presence of hydrogen bonds with the backbone, and its ability to fit closely within the substrate envelope (or consensus volume). Darunavir is potent against both wild-type and protease inhibitor-resistant viruses in vitro, including a broad range of over 4,000 clinical isolates. Additionally, in vitro selection studies with wild-type HIV-1 strains have shown that resistance to darunavir develops much more slowly and is more difficult to generate than for existing protease inhibitors. Clinical studies have shown that darunavir administered with low-dose ritonavir (darunavir/ritonavir) provides highly potent viral suppression (including significant decreases in HIV viral load in patients with documented protease inhibitor resistance) together with favorable tolerability. In conclusion, as a result of its high binding affinity for and overall fit within the active site of HIV-1 protease, darunavir has a higher genetic barrier to the development of resistance and better clinical efficacy against multidrug-resistant HIV relative to current protease inhibitors. The observed efficacy, safety and tolerability of darunavir in highly treatment-experienced patients makes darunavir an important new therapeutic option for HIV-infected patients.