Usage of reverse genetic techniques in the research area of the fundamental etiology of foot-and-mouth disease virus (FMDV), has resolved the issue about the function of viral gene of FMDV on genomic integer level. At present, a further recognition and apprehension for the molecular etiology of FMDV based on the development in reverse genetics was made. Combined with the research work in our labs, we reviewed international advances about the molecular pathogenic mechanism, the relationship between virulence and variation in the genomes, influencing factors for the viral replication, and the development of new-type gene vaccine of FMD in this article, and propose the potential research aspects in reverse genetics of FMDV in the future.