Vesicular stomatitis is an important viral disease of livestock in the Americas. It can affect ruminants, horses and pigs, causing vesicles, erosions and ulcers on the mouth, feet and udder. Although deaths are rare, these lesions can result in pain, anorexia and secondary bacterial mastitis, and some animals may lose their hooves after developing laminitis. Vesicular stomatitis viruses are endemic from southern Mexico to northern South America, but regularly spread north and south from these regions, causing outbreaks and epidemics. While these viruses are no longer endemic in the U.S., they are introduced periodically into the southwestern states, and can sometimes spread farther north. These outbreaks end after freezing temperatures kill the insect vectors that transmit vesicular stomatitis; however, the introduced viruses may overwinter for a year or two, re-emerging in the spring. Vesicular stomatitis is clinically indistinguishable from several other vesicular diseases of livestock including foot-and-mouth disease (FMD). Prompt diagnosis is important not only for containing vesicular stomatitis outbreaks, which can restrict international trade, but also in preventing major livestock diseases such as FMD from spreading undetected. People who work with vesicular stomatitis viruses or come in close contact with infected animals sometimes become infected and develop an influenza-like illness.