The clinical signs of foot-and-mouth disease (FMD) in cattle and pigs are those of an acute febrile vesicular illness. Persistent infection with FMDV (the carrier state) is considered to be a common sequel to both clinical and subclinical FMD in ruminants only, and is asymptomatic. Various factors influence the development and duration of persistent FMDV infection, including the genetics of the host and the viral challenge itself. The fear of FMDV carriers has led to restricted international trade in seropositive live ruminants. The mechanism employed by the virus to persist and evade immune elimination from the host is unknown. Despite the chronic stimulation of local IgA, the virus appears to persist in the epithelium of the soft palate and oropharynx. Evidence from in vitro work on persistently infected cell culture suggests a co-evolution of virus and cells, similar to some other picornavirus persistent infections. Thus despite an apparent antigenic stability of FMDV during persistence in vivo, it is possible that a tissue-specific variant is selected which can survive in a specific location without elimination. Whether this persisting virus represents a real source of infectious FMDV with the potential to cause patent disease in susceptible contact animals remains a mystery.