The rapid dissemination of chloroquine-resistant Plasmodium falciparum in West Africa has been well documented and represents a significant health threat to autochthonous populations. The methodical development of alternative chemotherapeutic agents demands that dispensing new antimalarial drugs (mefloquine, halofantrine, and artemisinine [qinghaosu]) be closely monitored in order to protect their clinical utility. Indeed, mefloquine-resistant strains of P. falciparum have been reported. We present data from experiments in vitro on the innate resistance of P. falciparum isolates to mefloquine as well as a disturbing observation of transient resistance to artemisinine. The implications for the extended efficacy of these new antimalarial drugs are addressed.