The discovery that the sesquiterpene peroxide yingzhaosu A (13) and 1,2,4-trioxane artemisinin (14) are active against chloroquine-resistant strains of Plasmodium falciparum, has opened a new era in the chemotherapy of malaria. In vitro and in vivo tests with synthetic structurally simpler trioxanes clearly demonstrate that much of the skeleton of 14 is redundant and that chirality is not required for activity. In addition, structure-activity relations and the search for the pharmacophore reveal that high antimalarial activity can be displayed by molecules which do not resemble the geometry of 13 and 14 at all. The possible mode of action of 13, 14, and synthetic peroxides is examined. They are believed to kill intraerythrocytic Plasmodium by interacting with the heme discarded by proteolysis of ingested hemoglobin. Complexation of heme with the peroxide bond followed by electron transfer generates an oxy radical that evolves to the ultimate parasiticidal agent. Experiments with ferrous reagents indicate that active peroxides including 14 and its congeners kill the parasite by alkylation with a sterically non-encumbered C-centered radical. However, another possibility is the involvement of a Fe(IV)=O species as the toxic agent. The review covers our own and other contributions to this timely topic and evaluates the different mechanisms proposed for the mode of action of peroxidic antimalarials.