Contamination of groundwater by arsenic from natural geochemical sources is at present a most serious challenge in the planning of large-scale use of groundwater for drinking and other purposes. Recent improvements in detection limits of analytical instruments are allowing the correlation of health impacts such as cancer with large concentrations of arsenic in groundwater. However, there are at present no known large-scale technological solutions for the millions of people—mostly rural—who are potentially affected in developing countries. An overall framework of combating natural resource degradation is combined with case studies from Chile, Mexico, Bangladesh and elsewhere to arrive at a set of strategic recommendations for the global, national and local dimensions of the arsenic “crisis”. The main recommendations include: the need for flexibility in the elaboration of any arsenic mitigation strategy, the improvement and large-scale use of low-cost and participatory groundwater quality testing techniques, the need to maintain consistent use of key lessons learned worldwide in water supply and sanitation and to integrate arsenic as just one other factor in providing a sustainable water supply, and the following of distinct but communicable tracks between arsenic-related developments and enhanced, long-term, sustainable water supplies.