Diagnosis and treatment of syphilis are challenging because of its variable clinical presentation and course and the lack of definitive tests of cure after treatment. This review of the most recent literature on the epidemiology, clinical manifestations, current diagnosis, and treatment of syphilis is focused toward clinicians who treat patients with this disease. Syphilis coinfection with human immunodeficiency virus is emphasized because it is increasingly common in the United States and affects the initial presentation, disease course, diagnosis, and treatment of syphilis. Of particular consequence is the effect of human immunodeficiency virus on the clinical diagnosis, prevalence, and course of neurosyphilis, one of the most serious consequences of syphilis infection.