Current understanding of the molecular basis of pathogenesis of foot-and-mouth disease (FMD) has been achieved through over 100 years of study into the biology of the etiologic agent, FMDV. Over the last 40 years, classical biochemical and physical analyses of FMDV grown in cell culture have helped to reveal the structure and function of the viral proteins, while knowledge gained by the study of the virus' genetic diversity has helped define structures that are essential for replication and production of disease. More recently, the availability of genetic engineering methodology has permitted the direct testing of hypotheses formulated concerning the role of individual RNA structures, coding regions and polypeptides in viral replication and disease. All of these approaches have been aided by the simultaneous study of other picornavirus pathogens of animals and man, most notably poliovirus. Although many questions of how FMDV causes its devastating disease remain, the following review provides a summary of the current state of knowledge into the molecular basis of the virus' interaction with its host that produces one of the most contagious and frightening diseases of animals or man.