From December 2014 to February 2016, a cluster randomized controlled trial was carried out in 60 health facility catchment areas along Lake Kariba in Zambia's Southern Province. The trial sought to evaluate the impact of four rounds of a mass drug administration (MDA) intervention with dihydroartemisinin-piperaquine (DHAP) or focal MDA with DHAP at the household level compared with a control population that received the standard of care. This study was the first randomized controlled trial with DHAP for MDA in sub-Saharan Africa and was conducted through a collaboration between the National Malaria Elimination Programme in the Zambian Ministry of Health, the PATH Malaria Control and Elimination Partnership in Africa, and the Center for Applied Malaria Research and Evaluation at Tulane University. This article serves as an introduction to a collection of articles designed to explore different aspects of the intervention. By describing the recent history of malaria control in Zambia leading up to the trial-from the scale-up of point-of-care diagnosis and treatment, vector control, and indoor residual spraying early in the twenty-first century, to the efforts made to sustain the gains achieved with that approach-it provides a rationale for the implementation of a trial that has informed a new national strategic plan and solidified malaria elimination as Zambia's national goal.