Despite the scale-up of interventions against malaria over the past decade, this disease remains a leading threat to health in Malawi. To evaluate the epidemiology of both Plasmodium falciparum infection and malaria disease, the Malawi International Center of Excellence for Malaria Research (ICEMR) has developed and implemented diverse and robust surveillance and research projects. Descriptive studies in ICEMR Phase 1 increased our understanding of the declining effectiveness of long-lasting insecticidal nets (LLINs), the role of school-age children in malaria parasite transmission, and the complexity of host-parasite interactions leading to disease. These findings informed the design of ICEMR Phase 2 to test hypotheses about LLIN use and effectiveness, vector resistance to insecticides, demographic targets of malaria control, patterns and causes of asymptomatic to life-threatening disease, and the impacts of RTS,S vaccination plus piperonyl butoxide-treated LLINs on infection and disease in young children. These investigations are helping us to understand mosquito-to-human and human-to-mosquito transmission in the context of Malawi's intransigent malaria problem.