Malaria is still the most common infectious cause of mortality and morbidity in Viet Nam as it is in many developing countries in the tropics. The presence of resistance to available antimalarials and compliance in the target population are factors that influence the choice of drugs and regimens. In order to develop an ideal treatment for malaria, we conducted several clinical trials in patients with the disease in different settings. The results of these trials suggest that a combination of single dose artemisinin (or its derivatives) and mefloquine is the most effective, safe and practical treatment for acute non-complicated malaria due to multidrug-resistant Plasmodium falciparum. Concerning severe and complicated malaria, parenteral or rectal multi-doses of artemisinin or analogues are recommended due to their rapid parasite clearance time and other possible anti-cytoadherence effects. With its rapid parasite clearance, very early treatment of uncomplicated cases with artemisinin (and derivatives), especially at a health post level may help to prevent the development of complications, consequently reducing the number of severe cases and the malaria mortality rate.