Rabies is a rare, yet nearly universally fatal diagnosis, responsible for over 59,000 deaths worldwide annually. Appropriate use of pre- and postexposure prophylaxis can eliminate the risk of developing rabies if administered according to the United States Centers for Disease Control and Prevention Advisory Committee on Immunization Practices guidelines. Though rabies is very rare, rapid recognition of potential exposures is vital to patient care and protection of public health. This review focuses on the challenges of managing patients who are at risk for or have had a potential rabies exposure, indications and guidelines for administering pre- or postexposure prophylaxis, and requirements for reporting, testing, and monitoring. Evidence regarding management of patients presenting with suspected clinical rabies is also reviewed.