Rabies is a zoonotic disease that is usually transmitted via virus-containing saliva from the bite of an infected animal. The virus infects the central nervous system, resulting in an acute, progressive, fatal encephalomyelitis. Since the mid–20th century, the incidence of rabies has significantly decreased in developed countries due to vaccination programs for dogs, cats, and other domestic animals. Additionally, measures are being taken to vaccinate wild animals. However, rabies remains a serious human health concern in the United States because there are reservoirs in bats and terrestrial wild animals such as raccoons, foxes, skunks, and mongooses. The canine rabies variant has been eliminated in the United States, but it is endemic in more than 150 countries and cause for human rabies exposure investigations in many others. Human infections can be prevented through avoiding exposure to animals with rabies, preexposure prophylaxis for individuals in high-risk occupations as well as travelers to high-risk countries, and postexposure prophylaxis (vaccination and rabies immunoglobulin administration) for individuals with known or suspected rabies exposure.