In accordance with international targets, the Uganda National Malaria Control Strategic Plan established specific targets to be achieved by 2010. For children under five, this included increasing the number of children sleeping under mosquito nets and those receiving a first-line antimalarial to 85%, and decreasing case fatality to 2%. This narrative review offers contextual information relevant to malaria management in Uganda since the advent of artemisinin combination therapy (ACT) as first-line antimalarial treatment in 2004. A comprehensive search using key words and phrases was conducted using the web search engines Google and Google Scholar, as well as the databases of PubMed, ERIC, EMBASE, CINAHL, OvidSP (MEDLINE), PSYC Info, Springer Link, Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Database of Systematic Reviews were searched. A total of 147 relevant international and Ugandan literature sources meeting the inclusion criteria were included. This review provides an insightful understanding on six topic areas: global and local priorities, malarial pathology, disease burden, malaria control, treatment guidelines for uncomplicated malaria, and role of the health system in accessing antimalarial medicines. Plasmodium falciparum remains the most common cause of malaria in Uganda, with children under five being most vulnerable due to their underdeveloped immunity. While international efforts to scale up malaria control measures have resulted in considerable decline in malaria incidence and mortality in several regions of sub-Saharan Africa, this benefit has yet to be substantiated for Uganda. At the local level, key initiatives have included implementation of a new antimalarial drug policy in 2004 and strengthening of government health systems and programs. Examples of such programs include removal of user fees, training of frontline health workers, providing free ACT from government systems and subsidized ACT from licensed private outlets, and introduction of the integrated community case management program to bring diagnostics and treatment for malaria, pneumonia and diarrhea closer to the community. However despite notable efforts, Uganda is far from achieving its 2010 targets. Several challenges in the delivery of care and treatment remain, with those most vulnerable and living in rural settings remaining at greatest risk from malaria morbidity and mortality.