Syphilis is a potentially fatal infectious disease that has a long history of association with psychiatry. Recent developments in epidemiology, diagnosis, and treatment guidelines warrant a review of the current relationship of syphilis to clinical psychiatry. After a recent peak of incidence in the United States, syphilis is once again on the decline. Although the prevalence of syphilis remains endemic in certain locations, it has been targeted for elimination. Meanwhile, diagnostic testing remains complex and imperfect, especially for the detection of late stages of infection and neurosyphilis. The U.S. Public Health Service recently revised guidelines for the evaluation and management for syphilis. This paper discusses these developments and their specific implications to psychiatric practice. The likelihood of discovering previously unsuspected cases through screening and recommendations on high-risk groups to screen are discussed. A case example illustrates some of the key concepts.