Syphilis is a chronic bacterial infection caused by Treponema pallidum that is endemic in low-income countries and and occurs at lower rates in middle-income and high-income countries. The disease is of both individual and public health importance and, in addition to its direct morbidity, increases risk of HIV infection and can cause lifelong morbidity in children born to infected mothers. Without treatment the disease can progress over years through a series of clinical stages and lead to irreversible neurological or cardiovascular complications. Although syphilis is an ancient disease and the principles of recommended management have been established for decades, diagnosis and management are often challenging because of its varied manifestations and difficulty in interpretation of serological tests used to confirm diagnosis and evaluate response to therapy. In North America and western Europe, incidence of syphilis has increased dramatically in the past decade among men who have sex with men, particularly those with coexistent HIV infection. Only one drug, penicillin, is recommended for syphilis treatment and response to therapy is assessed based on changes over months in serological test titres. Treatment for patients who cannot receive penicillin and management of patients who do not serologically respond to treatment are common clinical problems.