Young African children living in high transmission areas suffer the greatest burden of malaria. In most African countries, such as Uganda, the only current preventive measure against malaria in high transmission settings is the use of insecticide treated bednets (ITNs). Preliminary data show that even in the setting of ITN use, young children living in a high transmission setting suffer almost 4 episodes of clinical malaria per year, highlighting the need for new preventive strategies. Chemopreventive strategies offer a potential means of reducing the burden of malaria among young children living in a high transmission setting. This study will compare the efficacy and safety of 3 promising chemopreventive strategies (monthly dihydroartemisinin-piperaquine, monthly sulfadoxine-pyrimethamine, daily trimethoprim-sulfamethoxazole) with the current standard of no chemoprevention and will be conducted in two distinct patient populations: 1) HIV-unexposed children (HIV-uninfected children born to HIV-uninfected mothers) and 2) HIV-exposed children (HIV-uninfected children born to HIV-infected mothers). The intervention will begin in HIV-unexposed children when they reach 6 months of age, the time at which the incidence of malaria begins to increase, and will be continued until the children reach 24 months of age, which prior data suggest is when the incidence of malaria begins to decline due to the development of semi-immunity. In addition, study participants will be followed for one additional year following chemopreventive therapy to examine for "rebound" in the incidence of malaria following our intervention. HIV-exposed children will begin the intervention when they have completed breastfeeding and have been confirmed to remain HIV-uninfected. The intervention will continue until study participants reach 24 months of age and then the study participants will be followed for an additional year to examine for rebound in the incidence of malaria. It is anticipated that the results of this study will provide valuable comparative data on the effect of different chemopreventive strategies on malaria incidence in two distinct patient populations at high risk for malaria. In addition it is anticipated the results of this study will provide insight into the development of naturally acquired antimalarial immunity in the setting of chemopreventive therapy that will differ in terms of the drug regimens, the age at which the intervention is started, and the HIV status of the mothers.