The rabies virus is transmitted through exposure to infected saliva during either a bite or direct contact with mucosal tissues. Infection with this virus results in a progressive encephalitis, ultimately leading to coma, end-organ damage, and death. Because rabies-associated mortality is strikingly high, preventing viral transmission associated with an exposure is paramount. Fortunately, 2 available options exist for this purpose and include the rabies vaccine and the associated immunoglobulin. Patients presenting for consideration of rabies postexposure prophylaxis constitute a frequent complaint seen in the emergency department (ED) in most geographical areas. Management of these patients should be guided by an accurate and thorough discussion of the circumstances surrounding their exposure to attain maximum pharmacological benefit and avoid viral transmission. This article provides an overview of the practice recommendations surrounding rabies virus prophylaxis and their associated pharmacological characteristics in the ED.