Rates of primary, secondary, and congenital syphilis are increasing in the United States, and reversing this trend requires renewed vigilance on the part of family physicians to assist public health agencies in the early detection of outbreaks. Prompt diagnosis of syphilis can be challenging, and not all infected patients have common manifestations, such as a genital chancre or exanthem. The U.S. Preventive Services Task Force recommends screening for syphilis in all patients at increased risk, particularly those who reside in high-prevalence areas, sexually active people with HIV infection, and men who have sex with men. Other groups at increased risk include males 29 years or younger and people with a history of incarceration or sex work. All pregnant women should be screened for syphilis at the first prenatal visit, and those at increased risk should be screened throughout the pregnancy. The Centers for Disease Control and Prevention recommends the traditional screening algorithm for most U.S. populations. Penicillin is the preferred treatment across all stages of syphilis, although limited research suggests a possible role for other antibiotics in penicillin-allergic patients with primary or secondary syphilis. Pregnant women with syphilis who are allergic to penicillin should undergo penicillin desensitization before treatment.