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Rates of primary and secondary syphilis have increased in the past decade, warranting renewed attention to the diagnosis and treatment of this disease. Men who have sex with men are particularly affected; however, increases in infection rates have also been noted in women, as well as in all age groups and ethnicities. Physicians need to vigilantly screen high-risk patients. The concurrent rise in congenital syphilis also requires special attention and reemphasizes the need for continued early prenatal care and syphilis screening for all pregnant women. Syphilis infection in patients coinfected with human immunodeficiency virus has also become more common. New experimental diagnostic approaches, including using the B cell chemoattractant chemokine (CXC motif) ligand 13 as a cerebrospinal fluid marker, may help identify suspected neurosyphilis cases. Additionally, point-of-care immunochromatographic strip testing has been suggested for screening high-risk populations in developing countries. Nontreponemal screening tests followed by treponemal confirmatory tests continue to be standard diagnostics; however, interpreting false-negative and false-positive test results, and identifying serofast reactions, can be challenging. Although doxycycline, tetracycline, ceftriaxone, and azithromycin have been used to successfully treat syphilis, penicillin remains the drug of choice in all stages of infection and is the therapy recommended by the Centers for Disease Control and Prevention. Close follow-up is necessary to ensure treatment success.