Vesicular stomatitis is a disease of livestock caused by some members of the Vesiculovirus genus (Family Rhabdoviridae), two of which are called 'vesicular stomatitis virus'. Clinical disease presents as severe vesiculation and/or ulceration of the tongue, oral tissues, feet, and teats, and results in substantial loss of productivity. Except for its appearance in horses, it is clinically indistinguishable from foot-and-mouth disease. Unlike foot-and-mouth disease, it is very infectious for man and can cause a temporarily debilitating disease. Vesicular stomatitis occurs seasonally every year in the southeastern USA, southern Mexico, throughout Central America and in northern South America, and emerges from tropical areas to cause sporadic epidemics in cooler climates during the summer months. Other Vesiculoviruses are endemic in India and Africa. Vesiculoviruses are arthropod-borne and it is possible they are actually well adapted insect viruses that incidentally infect mammals. Vesiculoviruses are relatively simple, having a linear, single stranded, negative sense RNA genome encased in a bullet-shaped virion made from only five proteins. Upon infection of cultured cells, viral products turn off cellular gene expression and seize the entire metabolic potential of the cell. They also depolymerize the cytoskeleton to cause rapid tissue destruction. Virus infection in animals provokes interferon and nitric oxide responses, which quickly control viral replication, and an antibody response that prevents further viral replication. Vesiculovirus genome replication is error-prone, resulting in viral progeny containing many variants. This allows rapid adaptation. Nevertheless, vesicular stomatitis virus genomic sequences appear relatively stable within single endemic areas, and vary progressively on a North-South axis in the Western Hemisphere. Numerous important fundamental discoveries in immunology and virology have come from recent studies of vesicular stomatitis virus. However, these discoveries have not led to a safe and fully effective vaccine for man or beast. In the absence of a vaccine, the continual increase in rapid intercontinental travel, the increase in numbers and concentration of susceptible animals, the plasticity of the viral genome, and the underappreciation of vesiculoviruses as veterinary and zoonotic pathogens by regulators and biomedical researchers, are combining with potentially explosive consequences.