Malaria has plagued man throughout recorded history and results in the death of over two million people per year and increased morbidity. The importance of malaria in human history can be demonstrated by its impact on some of the major wars. Malaria may have caused the death of Alexander the Great, which brought to a close the rampage of his armies across Asia. Also, malaria was prevalent in the American Civil War. The invasion of Papua New Guinea by the Japanese across the Owen Stanley Ranges was affected greatly by malaria infection, as both sides lost large portions of their fighting capacity to the debilitating effects of the malaria parasite. Malaria had a lesser effect on modern wars, such as the Vietnam war, due to the availability of effective antimalarial drugs, however; the ability of the malaria parasite to develop resistance to these chemotherapeutic agents resulted in the search for new alternatives, firstly; by workers in the United States of America resulting in the development of mefloquine and halofantrine and, secondly; by the Chinese who developed artemisinin.

The major control strategy of malaria is through chemotherapy, however; the malaria parasite has managed to develop resistance to virtually all of the currently available drugs causing a crisis in the use and deployment of these compounds for prophylaxis and treatment of this disease. This chapter will address what is known about the mechanism of action of the important antimalarial drugs and the strategies that the parasite has developed to evade the effect of many of these drugs. Not all is known about the exact mechanism of action and resistance in the malaria parasite and there are points of disagreement on some of these aspects, and where this is the case, I will try to present each view in a balanced way.