HIV-1 fusion inhibitors are a new class of anti-HIV compounds, which block the entry of HIV into target cells through preventing the fusion between viral and cell plasma membrane and thus interrupt the  initial steps of viral replication.  T-20 (enfuvirtide), which has been clinically approved as the first fusion    inhibitor of HIV-1 by U.S. FDA in 2003, can suppress replication of HIV variants with multi-drug resistance to reverse transcriptase and protease inhibitors.  Peptides and small molecules display potent anti-HIV fusion   activities by targeting gp41 thus inhibit its fusogenic function.  In recent years, with the development of studies on the molecular mechanism of HIV membrane fusion process and the function of gp41, many new fusion    inhibitors are found and some have been in advanced clinical trials.  This review discusses recent progress in the development of HIV-1 fusion inhibitors targeting the gp41.