There has been a relentless increase in resistance of malaria parasites to conventional antimalarial drugs, including chloroquine, sulfadoxine-pyrimethamine and mefloquine. In response to this situation, short-course artemisinin-based combination therapies (ACTs) have been developed. The World Health Organization has endorsed ACT as first-line treatment where the potentially life-threatening parasite Plasmodium falciparum is the predominant infecting species. ACTs combine the rapid schizontocidal activity of an artemisinin derivative (artesunate, artemether or dihydroartemisinin) with a longer-half-life partner drug. Although the use of chloroquine and sulfadoxine-pyrimethamine as partners in ACT improves their efficacy, this may only have value as a short-term measure in patients with a degree of immunity to malaria. Alternative currently available partner drugs include mefloquine, lumefantrine and piperaquine. Artesunate-mefloquine is highly effective but is expensive and side effects (mainly neurotoxicity) can be problematic. Artemether-lumefantrine, the only ACT available in Australia, appears less effective than artesunate-mefloquine and needs to be administered with food to ensure adequate bioavailability. Dihydroartemisinin-piperaquine is highly effective, well tolerated and relatively inexpensive. The goal of potent, safe, easy-to-administer and inexpensive ACTs may see trioxolanes in place of artemisinin derivatives, as well as novel partner drugs such as pyronaridine or naphthoquine, in the future.