Fever of unknown origin is a topic that has enduring interest to physicians. Prolonged fevers of infectious etiology were of particular concern to the ancient physician. This overview of prolonged fevers in antiquity focuses on malaria and typhoid fever as the primary infectious causes. By studying texts from Mesopotamian, Greek, and Roman physicians and observers of disease, it is possible to determine the likely etiology of many of these ancient plagues. The historical import of these diseases should not be overlooked, and it is for this reason that the prolonged fevers of antiquity have profound significance and enduring interest.