Vesicular stomatitis (VS) is an important disease of cattle, horses and pigs. The causal agent is an arbovirus; vesicular stomatitis virus (VSV) of which two distinct serotypes New Jersey (NJ) and Indiana (IN) have been described. The clinical signs in cattle and pigs are undistinguishable from foot-and-mouth disease (FMD), one of the most devastating viral infections of livestock. VSV is the most important cause of vesicular disease in FMD-free countries in the Americas, causing thousands of outbreaks every year from southern Mexico to northern South America. In the United States VS has two different patterns of occurrence; in the southeastern states (Georgia, Alabama, North Carolina and South Carolina) a pattern of yearly occurrence of clinical cases in livestock was reported from early 1900s until the mid 1970s. Since then, viral activity in the region has been focal and limited to isolated wildlife populations. In contrast in the southwestern states (New Mexico, Arizona, Utah and Colorado) VS outbreaks have occurred sporadically at approximately 10-year intervals, with the last cycle of activity occurring from 1995 to 1998. Phylogenetic analyses of VSV have shown that distinct viral lineages occur in the southwestern and southeastern US. Furthermore, in the last 70 years each sporadic outbreak in the Southwest was associated to viral lineages distant from those causing previous outbreaks in the US but closely related to viruses maintained in endemic areas of Mexico. This pattern of viral occurrence contrasts with that observed in endemic areas in Central and South America where viral genetic lineages are maintained in specific ecological areas over long periods of time. The phylogenetic data together with the geographical and temporal distribution of outbreaks indicate that VSV does not have a stable endemic cycle in the western United States.