[Truncated abstract] Malaria is the most important parasitic disease of man. Of the five species known to infect humans, Plasmodium falciparum causes most deaths and illness, especially when it affects children and pregnant women living in highly endemic areas of the rural tropics. Pharmacological therapies for malaria must be optimised for these groups and must be practical for administration in critically ill patients in remote settings. The clinical studies in this thesis evaluated the clinical pharmacology of modern antimalarial treatments in a Melanesian population exposed to highly endemic malaria. The clinical studies were conducted between March 2001 and June 2007, with final data analysis completed by mid-2008. They aimed to evaluate key pharmacokinetic, parasitological, host genetic and socio-cultural determinants of treatment effectiveness in children with uncomplicated and severe malaria and in pregnant women. A multi-centre study of children with uncomplicated malaria evaluated the efficacy of four treatment regimens, including three artemisinin combination treatments. PCR corrected recrudescence rates by day 42 were 81.5%, 85.4%, 88.0% and 95.2% for chloroquine + sulphadoxine-pyrimethamine, artesunate + sulphadoxine-pyrimethamine, dihydroartemisinin-piperaquine (DHA-PQ) and artemether-lumefantrine (AL), respectively. Determinants of efficacy in the DHA-PQ group included day 7 piperaquine (PQ) levels and baseline parasitaemia. Therefore, the worse than expected efficacy in this group may have been partly due to the high parasitaemias commonly seen in this population. ... Preliminary data suggested a protective effect of the erythrocyte polymorphism caused by the glycophorin C mutation against cerebral malaria. These studies also evaluated key pharmacokinetic, host genetic and socio-cultural determinants of the likely effectiveness of a novel pharmaceutical approach using artesunate suppositories for severe malaria. These demonstrated favourable absorption characteristics, clinical efficacy, safety and patient/community acceptability. Contrary to previous data, no evidence was found to suggest that the pharmacokinetic profiles or efficacy of artemisinin derivatives are likely to be compromised by a high prevalence of thalassaemia in this population. However, their highly variable bioavailability raises questions regarding the consistency of therapeutic response. Given the favourable efficacy and socio-cultural acceptability of rectal artesunate demonstrated in these studies, the PNG Ministry of Health has decided to add artesunate suppositories to its national pharmacopoeia and incorporate them into standard treatment recommendations. A final study compared the pharmacokinetics of chloroquine, sulphadoxine and pyrimethamine in pregnant, versus non-pregnant women. This demonstrated significantly lower concentrations of all three drugs and active metabolites in the pregnant group, due to a combination of effects on either volume of distribution, clearance and elimination half-life. It suggests that significant dosage alterations are necessary to optimise therapy in pregnant women.