More cases of primary and secondary syphilis were reported in 1989 than in any year since 1949. Incidence is rising despite four decades of penicillin therapy. The spread of syphilis has been linked to the rising incidence of drug use, especially of crack cocaine. Observations in patients coinfected with human immunodeficiency virus have raised questions about the adequacy of penicillin and prompted a reevaluation of syphilis therapy. Efforts to control the epidemic have brought needed attention to improving health care delivery to persons at risk for syphitis.