This study follows the observation that chloroquine-resistant malaria may have returned to Malawi, 10 years after its use was eliminated. There is growing consensus that combination chemotherapy should be the rule in malaria treatment to deter the development of drug resistance and possibly also decrease malaria transmission. As sulfadoxine-pyrimethamine (SP) failure rates increase, the reintroduction of chloroquine in Malawi in combination with highly effective rapidly acting drugs such as artesunate and chlorproguanil-dapsone should be considered, and would likely extend the useful life span of each of the drugs. In preparation for a longitudinal clinical trial of chloroquine alone and SP in combination with other drugs, a preliminary trial will be conducted to compare the anti-malarial efficacy of chloroquine versus SP, the standard treatment in Malawi. This is a randomized, open-label clinical trial to compare the antimalarial efficacy of chloroquine versus SP among children with uncomplicated malaria in Blantyre, Malawi. In this study, 210 peri-urban children will be randomly assigned to receive standard dosing of either chloroquine or SP. Follow up will consist of visits on days 2, 3, 7, 14, 21 and 28, according to the standard World Health Organization protocol. Because chloroquine has not been used to treat malaria in Malawi for over a decade, special safety precautions will be taken at the beginning of the study. The first 30 participants in each arm will remain at the Health Centre under continuous observation of the medical staff to monitor response to therapy until they are afebrile for 12 hours and have two consecutive negative 12-hourly blood smears. Observation in an inpatient setting will also help to avoid potential bias due to more intense follow-up of the hospitalized group. A Safety Monitoring Committee (SMC) will meet after the first 30 participants have been enrolled in each arm to determine if the study should stop continuous observation and proceed with out-patient follow up only. All participants will be followed for 28 days to monitor for late therapeutic or parasitologic failure. The primary study objective is to assess the efficacy of chloroquine compared with standard SP therapy, in treating malaria in Malawi, where chloroquine has not been used for over 10 years and to compare it to the efficacy of standard therapy with SP. The secondary study objective is to assess the effect of the re-introduction of chloroquine on the molecular markers associated with chloroquine resistance. The primary study endpoint is the rates of adequate clinical and parasitologic response to therapy. The secondary study endpoints are: (1) rates of early and late therapeutic failure; (2) rates of early and late parasitologic failure; (3) prevalence of chloroquine-resistance conferring pfcrt K76T mutation in pre-treatment infections; (4) rates of pre- and post-treatment pfcrt K76T mutation in cases of chloroquine treatment failure; (5) prevalence of SP-resistance conferring dhfr/dhps mutations in pre-treatment infections; (6) rates of pre- and post-treatment dhfr/dhps mutations in cases of SP treatment failure; (7) clearance time of parasitemia; (8) clearance time of fever; and (9) presence of post-treatment anemia.