Malaria remains the most serious and deadly parasitic disease, affecting millions of people mostly in the poorest countries in the world. With no vaccine likely in the foreseeable future, drugs remain the best means of controlling the disease. Plants have provided most of the antimalarial drugs so far and it is likely that more antimalarial drugs will be discovered in this way. A previous study on South African plants yielded very good results on the extract level. In this study Croton steenkampianus leaf extract was selected for isolation of active principles. Bio-guided fractionation of the extract was done on silica column chromatography and Sephadex column chromatography. Five compounds, two favonoids, a triterpene and two new diterpenes, with a novel skeleton were isolated. Compounds were identified with NMR, MS and X-ray crystallography. Antiplasmodial activity of the compounds varied from moderate to excellent, with crotrene A having excellent activity. Further studies on the antimalarial potential of this compound are planned. Cytotoxicity of compounds and extract were determined against human lymphocytes. Results obtained had an ID50 between >16,61 µg/ml. The therapeutic indexes were between 2.75 and 55.18, showing poor to moderate selectivity towards Plasmodium. Crotrene A had the best therapeutic index and more detailed studies on its cytotoxicity are necessary. Resistance to antimalarial drugs is a major problem in effective treatment of the disease. One way of overcoming this problem is combination drugs working synergistically. Chloroquine the most affordable antimalarial drug was combined with the isolated compounds. Two compounds showed synergistic activity with crotrene A having excellent activity, completely reversing chloroquine resistance. This combination of drugs showed no synergistic cytotoxic effects and its potential as a drug will be further investigated. The mode of action of antimalarial drugs can provide useful information about the long term potential and the likelihood of resistance development. Crotrene A was subjected to a basic test to determine a possible mode of action. Results showed a marked effect in the early phase of development (rings). The results suggest a very potent mode of action able to reduce the amount of parasites quickly and this holds promise for further development of this compound.