OVER THE LAST 100 years, rabies in the United States has changed dramatically. More than 90% of all animal rabies cases reported annually to the CDC now occur in wildlife, whereas before 1960 the majority were in domestic animals. The principal rabies hosts today are wild carnivores and bats infected with several viral variants. Annual human deaths have fallen from more than a hundred at the turn of the century to one to two per year despite major outbreaks of animal rabies in several geographic areas. Modern day prophylaxis has proven nearly 100% successful; most human fatalities now occur in people who fail to seek medical treatment, usually because they do not recognize a risk in the animal contact leading to the infection. Although these human rabies deaths are rare, the estimated public health costs associated with disease detection, prevention, and control have risen, exceeding millions of dollars each year. Cost considerations must be weighed along with other factors in addressing issues such as the appropriate handling of nontraditional and exotic pets, future guidelines for rabies prophylaxis, and novel methods of disease prevention.