The epitome of the One Health paradigm—and of its shortcomings—rabies has been known to humankind for at least 4000 years. We review the evolution through history of concepts leading to our current understanding of rabies in dogs and humans and its prevention, as transmitted by accessible and surviving written texts. The tools and concepts currently available to control rabies were developed at the end of the 19th Century, including the first live, attenuated vaccine ever developed for humans and the first post-exposure prophylaxis (PEP) regimen. No progress, however, has been made in etiological treatment, leaving clinicians who provide care to animals or patients with symptomatic rabies as powerless today as their colleagues in Mesopotamia, 40 centuries ago. Rabies remains to date the most lethal infectious disease known to humans. Widespread access to timely, effective, and affordable PEP in rural areas of developing countries is urgently needed.