Abstract: HIV-1 protease inhibitors play a very important role in AIDS chemotherapy，but with the rapid emergence of drug resistance as a result of the residue mutation of HIV-1 protease，developing effective protease inhibitors with superior activity against drug-resistant variants is becoming the research hotspot in AIDS drug design. Meanwhile，some molecular designing strategies of anti-drug-resistant HIV-1 protease inhibitors were put forward and applied to develop anti-AIDS drugs.The purpose of the research is introducing these molecular designing strategies to develop potent HIV-1 protease inhibitors to combat drug resistance，including substrate envelope hypothesis，strengthening the binding of inhibitors to HIV-1 protease and searching inhibitors acting in novel sites of HIV-1 protease.