The epidemiology of rabies in the United States has changed substantially during the last half century, as the source of the disease has changed from domesticated animals to wildlife, principally raccoons, skunks, foxes, and bats. Moreover, the changes observed among affected wildlife populations have not occurred without human influence. Rather, human attraction to the recreational and economic resources provided by wildlife has contributed to the reemergence of rabies as a major zoonosis. Although human deaths caused by rabies have declined recently to an average of one or two per year, the estimated costs associated with the decrease in deaths amount to hundreds of millions of dollars annually. In future efforts to control rabies harbored by free-ranging animal reservoirs, public health professionals will have to apply imaginative, safe, and cost-effective solutions to this age-old malady in addition to using traditional measures.