The burden of malaria has decreased dramatically within the past several years in parts of sub-Saharan Africa, following the scale-up of interventions supported by the Roll Back Malaria Partnership, the President's Malaria Initiative and other partners. It is important to appreciate that the reductions in malaria have not been uniform between and within countries, with some areas experiencing resurgence instead. Furthermore, while interventions have greatly reduced the burden of malaria in many countries, it is also recognized that the malaria decline pre-dated widespread intervention efforts, at least in some cases where data are available. This raises more questions as what other factors may have been contributing to the reduction in malaria transmission and to what extent. The International Center of Excellence for Malaria Research (ICEMR) in Southern Africa aims to better understand the underlying malaria epidemiology, vector ecology and parasite genomics using three contrasting settings of malaria transmission in Zambia and Zimbabwe: an area of successful malaria control, an area of resurgent malaria and an area where interventions have not been effective. The Southern Africa ICEMR will capitalize on the opportunity to investigate the complexities of malaria transmission while adapting to intervention and establish the evidence-base to guide effective and sustainable malaria intervention strategies. Key approaches to attain this goal for the region will include close collaboration with national malaria control programs and contribution to capacity building at the individual, institutional and national levels.