Diarrhea continues to stand among the most important causes of global morbidity and mortality in children under 5 years of age. Although the introduction of oral rehydration and other case-management strategies have reduced acute diarrhea fatalities, many of the survivors develop persistent diarrhea and/or deficiencies of growth and cognition. Thus understanding the true global burden of diarrhea requires attention to acute diarrhea as well is its sequelae. To understand the etiology of moderate to severe diarrhea among children in high mortality areas of sub-Saharan Africa and south Asia we performed a comprehensive case-control study of children under 5 years of age at seven sites. Each site employed an identical case-control study design and each utilized a uniform comprehensive set of microbiological assays to identify the likely bacterial, viral and protozoal etiologies. Results of the studies will inform diarrhea prevention and management efforts worldwide.