Intermittent preventive treatment in infants (IPTi) is an effective and safe malaria control strategy. However, it remains unclear what antimalarials should be used to replace sulfadoxine-pyrimethamine (SP) when and where SP is no longer an effective drug for IPTi. Work recently conducted in Tanzania, combined with the findings of previous studies, indicates that IPTi is essentially intermittent chemoprophylaxis; consequently, long-acting antimalarials that provide a long period of post-treatment prophylaxis will be the most effective alternative to SP. However, because of concerns about development of drug resistance, new combinations of long-acting drugs are urgently needed.