The paper challenges the conventional wisdom that water and sanitation improvements and other preventive health interventions are always a wise economic investment. Costs and benefits are presented for six water, sanitation, and health programs—handwashing, sanitation, point-of-use filtration and chlorination, insecticide-treated bed nets, and cholera vaccination. Model parameters are specified for a range of conditions that are plausible for locations in developing countries. We find that the parameter findings needed for such cost-benefit calculations are not available for setting global priorities. We reflect on the implications of our findings for more “evidence-based” planning of public health and development interventions.