Infection with HIV-1 causes the pandemic disease of AIDS in an estimated 30 million people. The viral protease has proved a successful target for AIDS therapy, and current effective therapy uses a selection from eight protease inhibitors in combination with other antiviral drugs. The antiviral protease inhibitors were developed over the past 15 years based on knowledge of the molecular structure of the protease, its substrate specificity and the mode of binding of inhibitors. Today, drug resistance has become a major challenge in AIDS therapy. Consequently, in the combat against drug resistance new antiviral protease inhibitors are being developed from structure-guided designs. These new drugs, such as darunavir, demonstrate high affinity binding to resistant mutants of HIV protease, and provide high genetic barriers to resistance. Recent developments are described in these structure-guided designs for antiviral therapy based on targeting the HIV-1 protease and its drug resistant mutants.