The number of primary and secondary syphilis cases in young women rose dramatically in the late 1980s and early 1990s, due to illicit drug use and the exchange of drugs for sex. Of infants born to mothers with primary or secondary syphilis, up to 50% will be premature, stillborn, or die in the neonatal period; further, most of these children are born with congenital disease that may not be apparent for years. While appropriate treatment of the pregnant female can prevent congenital syphilis, the major deterrent has been the inability to effectively identify these women and get them to undergo treatment. In determining a penicillin regimen, the clinician must consider the stage of maternal infection, the length of fetal exposure, and physiologic changes in pregnancy that can affect the pharmacokinetics of antibiotics. Treatment decisions may be further complicated in patients who are allergic to penicillin or infected with HIV. The pathogenesis of congenital syphilis is not completely understood, but placental invasion is the presumed major route. All women should be screened for syphilis with a nontreponemal test (eg, rapid plasma reagin [RPR] or venereal disease research laboratory [VDRL] test) in the first trimester. Those at high risk should be retested at 28 weeks and near delivery. Even with appropriate treatment of syphilis during pregnancy, fetal infection may still occur in up to 14% of cases. Treating syphilis during pregnancy can be difficult due to physiologic changes that can alter drug levels and the risk that drugs will induce uterine contractions or compromise the health of the fetus. While there are added risks and potential complications, treatment regimens parallel those in nonpregnant women.