Abstract The Southern Africa International Centers of Excellence for Malaria Research (ICEMR) has been highly successful, with 19 peer-reviewed publications of primary research findings at the time of this application, co- authorship on seven additional ICEMR-related reviews, and research findings that have been translated into policies. Through integrated studies of malaria epidemiology and vector bionomics in three different transmission settings in Zambia and Zimbabwe, we developed detailed understanding of the drivers of malaria transmission at each site, identified key barriers to control and elimination, and informed policy decisions to improve control strategies. In this renewal application, we will build upon the infrastructure, expertise and relationships developed by the Southern Africa ICEMR over the past six years to further advance malaria control and elimination in a critical geographic expanse, extending from a setting of highly seasonal malaria transmission in eastern Zimbabwe on the border with Mozambique, through the pre-elimination setting in southern Zambia, to the high transmission settings in northern Zambia and southeastern Democratic Republic of Congo (DRC). This region is the focus of intense malaria control and elimination efforts, including those of the President's Malaria Initiative, United States Agency for International Development, Bill & Melinda Gates Foundation and the Global Fund to Fight AIDS, Tuberculosis and Malaria as well as numerous smaller regional initiatives such as Elimination 8. No other research group in southern Africa has studied the barriers to control and elimination in such depth, duration and across such a range of transmission settings. Continuing and building upon the research activities of the Southern Africa ICEMR will be critical to the success of these investments and the control and elimination of malaria in southern Africa. Our theme is to address critical research questions on barriers to malaria control and elimination in Southern and Central Africa, specifically explanations for continued malaria in high, moderate and low transmission settings despite current public health interventions.