This review summarizes progress in treating severe and complicated malaria, which are global problems, claiming at least one million lives annually, and have been accompanied by advances in our understanding of the pathogenesis of severe malaria complications. New drugs such as intravenous artesunate (AS) and intramuscular artemether (AM) are improving outcomes and decreasing malaria deaths. Trials comparing AM to the traditional parenteral drug, quinine, have not demonstrated however convincing evidence of a mortality advantage for AM. The South East Asian Quinine Artesunate Malaria Trials (SEAQUAMAT), a multicenter, randomized, open-label study comparing AS with quinine showed that parenteral AS was shown to be associated with a 35% reduction in the risk of mortality compare to quinine, and is now the recommended treatment by the WHO for severe and complicated malaria in low-transmission areas and in the second and third trimesters of pregnancy, with almost all the benefit reported in those with high parasite counts. Artesunate is a semisynthetic derivative of artemisinin whose water solubility facilitates absorption and provides an advantage over other artemisinins because it can be formulated as oral, rectal, intramuscular, and intravenous preparations. Artesunate is rapidly hydrolyzed to dihydroartemisinin, which is the most active schizonticidal metabolite. Injectable AS results in a more rapid systemic availability of AS compared with intramuscular AM. This pharmacokinetic advantage may provide a clinical advantage in the treatments of severe and complicated malaria.