Plasmodium falciparum is one of the main parasitic pathogens worldwide. Artemisinin derivatives are the first-line antimalarial drug. Recently, Plasmodium falciparum has been found to be tolerant to the treatment with artemisinin derivatives and its combination with piperaquine in several countries and regions. Scientists have found gene mutations associated with resistance of Plasmodium falciparum to artemisinin derivatives; however the mechanism of piperaquine resistance remains to be further studied. This review sums up the epidemic status and mechanism research of the resistance of Plasmodium falciparum to artemisinin derivatives and piperaquine.