Experiments in animals have played an integral role in furthering basic understanding of the pathophysiology, host immune response, diagnosis, and treatment of infectious diseases. However, competing demands of modern-day clinical training and increasingly stringent requirements to perform animal research have reduced the exposure of infectious disease physicians to animal studies. For practitioners of infectious diseases and, especially, for contemporary trainees in infectious diseases, it is important to appreciate this historical body of work and its impact on current clinical practice. In this article, we provide an overview of some major contributions of animal studies to the field of infectious diseases. Areas covered include transmission of infection, elucidation of innate and adaptive host immune responses, testing of antimicrobials, pathogenesis and treatment of endocarditis, osteomyelitis, intra-abdominal and urinary tract infection, treatment of infection associated with a foreign body or in the presence of neutropenia, and toxin-mediated disease.