Despite strong efforts to control it, malaria remains a serious health problem in Madagascar with episodic unpredictable recrudescence. Local communities, especially those living in remote areas, rely on traditional medicine to treat the disease. Our research on ethnobotany-based malaria chemotherapy began in the 1990s following the sudden resurgence of the disease. Our work was first focused on drugs that could reverse chloroquine resistance in malaria. This led to the discovery of naturally occurring chemosensitizers, namely, the herveline series and the malagashanine series. Moving to the hepatic stage, we isolated a new alkaloid named tazopsine which was selectively active against the liver stage of the malaria parasite. Malagashanine was used as a biochemical tool for the understating of chloroquine resistance and its reversal. The alkaloid strychnobrasiline was used as a starting material for various chemical modifications. These investigations, together with careful examination of structures of naturally occurring and synthetic chemosenitizers, gave clues for the design and synthesis of new chemosensitizers. Gallic acid was found to enhance the antiplasmodial activities of phenolic compounds, and this property led to the identification of chromophores that may interact with the fatty acid II biosynthesis. After a critical analysis of previous investigations on malaria, and based on our preliminary results, we propose a holistic approach which includes killing the parasites, boosting the immune system and managing the inflammatory process. © 2012 Springer-Verlag Berlin Heidelberg. All rights are reserved.