Although prenatal diagnosis and prenatal and neonatal therapy of congenital toxoplasmosis are available, there is controversy concerning the effectiveness of prophylaxis to prevent placental transmission. Experimental, parasitological and clinical data suggest a "window of opportunity" following maternal infection. Among medications active against T. gondii, mainly spiramycin (Spy) and pyrimethamine + sulfonamide combinations (P-S) have been evaluated. Results from observational studies suffered treatment bias, since prescriptions differed according to the gestational age at seroconversion, which is the major risk factor for transmission, and many lacked precise timing. Some large retrospective studies found no difference in transmission according to prophylactic treatment, but transmission was lower when treatment started promptly after maternal seroconversion. A few recent studies adjusting for timing of infection observed lower transmission in case of P-S than other or no prophylaxis. In the only randomized controlled trial, transmission was lower with P-S than S (18.5% vs. 30%, p = 0.147) ; this association was strengthened when the treatment was started within 3 weeks of seroconversion, and the incidence of fetal cerebral ultrasound signs was significantly reduced in the P-S group. Rapid initiation of prophylactic therapy following maternal infection, which is usually asymptomatic, requires systematic screening for maternal seroconversion during pregnancy.