Abstract Despite progress in reducing malaria morbidity and mortality in much of southern Africa, including Zambia and Zimbabwe, challenges persist. In some regions, such as Nchelenge District in northern Zambia, malaria transmission remains high despite implementation of standard case management and vector control measures. Across the border in the Democratic Republic of Congo, only limited vector control interventions have been implemented. Further south, in Mutasa District in eastern Zimbabwe, recent gains in malaria control and elimination are threatened by emerging insecticide resistance and cross-border malaria transmission. The potential risk of emergent drug resistance is a threat to regional malaria control. Importantly, increased resources and efforts will be allocated to reduce malaria transmission in high transmission settings such as Luapula Province in northern Zambia and the adjacent Katanga Province in the Democratic Republic of Congo (DRC), and to prevent resurgence and eliminate malaria in areas with seasonal transmission such as eastern Zimbabwe. The Southern and Central Africa ICEMR will address three research questions of critical importance to malaria control in these epidemiological settings: 1) patterns and drivers of moderate to high level malaria transmission; 2) specific barriers to control, including insecticide resistance, antimalarial drug resistance and cross-border malaria transmission; and 3) the optimal combination of malaria control interventions.