Entry of enveloped viruses into host cells requires fusion of the viral envelope with a cellular membrane. This step is mediated by viral glycoproteins that undergo a dramatic conformational change. Recent advances in structure and function of the fusion proteins of the class Ⅱ viruses, Rhabdoviruses and Herpesviruses were described. Proteomics computational analyses to locate the functional domain of fusion protein were introduced. The fusion proteins of class Ⅱ and class Ⅰ viruses differ radically in their initial structures but refold toward similar final conformation (trimer of hairpin). The Rhabdoviruses and Herpesviruses have a novel fold combining features of fusion proteins from class Ⅰ and class Ⅱ. The fusion proteins of these viruses have a different conformation change and mediate a different fusion process, therefore, the proteins belong to a novel class of fusion proteins. The potent inhibitor of virus entry should be new strategies for developing antiviral drugs.