This supplement to the American Journal of Tropical Medicine and Hygiene (AJTMH) (Am. J. Trop. Med. Hyg., 77(6 Suppl), 2007) is entitled "Defining and Defeating the Intolerable Burden of Malaria III: Progress and Perspectives." It is the third volume of a series of AJTMH supplements aimed at shedding light on the scientific, technical, programmatic, and developmental issues related to the malaria burden and its decrease. This volume provides updates on the malaria situation, describes challenges facing the malaria control programs, and suggests new approaches and tools, which, if made available and accessible to the populations in need, would avert millions of deaths and save billions of dollars.