Recent studies have shown that enveloped virus might adopt a similar molecular mechanism of fusion in which two types have been proposed. In TypeⅡ，flavivirus is examples, its fusion mechanism is not similar with typeⅠ and is not understood enough. In TypeⅠ which is the subject of this review and HIV and influenza are its good examples, the attachment glycoprotein of virus binds receptor/s and triggers the conformational change of the fusion protein (attachment protein and fusion protein could be one with two subunits), finally, adopts its most stable fold, the trimer-of-hairpins. The membrane fusion process leads to the release of viral proteins and the RNA genome into the host cell, initiating an infection cycle.The fusion mechanism involves an intermediate conformational state that can be targeted by therapeutic strategies. Holding the fusion process in the middle would stop the virus entry. The potent and effective therapeutic interventions of virus entry should be possible from a recent clinical trial success of a peptide inhibitor for HIV, Enfuvirtide or T20.