Drug combination therapy is derived from the premise that administering two or more drugs at the same time that have synergism or additive effects with independent efficacy and different targets will lead to enhanced efficacy and diminished drug resistance. As medicinal chemistry and biological knowledge of the malaria parasite advances, drug combinations for treatment of malaria have become the standard of care. A number of efforts have been made over the years to quantitate the relationship between dose and effect of each drug partner alone and the dose effect relationship of the drugs in combination and to assess whether a drug combination provides a synergistic effect. Antimalarial drug combination therapy (CT) involves the administration of two or more blood schizonticidal drugs each with a separate and different mechanism of action and each targeted to a different parasite protein or process. As described here, drug combinations for antimalarial treatment that include a non-antimalarial drug provided to enhance antimalarial efficacy of a blood schizonticidal drug do not qualify as combination therapy. Artemisinin based combination therapies (ACTs) have been adopted in Asia since 1992 and in Africa since 2000, and these drug combinations have been shown to improve vastly antimalarial treatment efficacy. ACTs are now first-line treatment for P. falciparum malaria globally; they are more effective than non-artemisinins combinations or monotherapies, and ACTs reduce the chances of development of parasite drug resistance. ACTs demonstrate certain key performance parameters associated all of which are related to the unique activities of the artemisinin component, and these features include:1) rapid reduction of the biomass of the parasite; 2) swift clearance of parasites; 3) prompt resolution of patient symptoms; 4) successful treatment against multidrug-resistant P. falciparum and 5) decrease in incidence of gametocyte carriage, which, in theory, will result in turn in reduction of transmission of drug resistant parasites bearing drug resistance alleles.