This Case Profile first provides a concise scientific overview of the advances in understanding of the Guarani Aquifer System generated by the GEF-supported Guarani Aquifer–Sustainable Development & Environmental Protection Program of the Mercosur Nations of Argentina, Brasil, Paraguay & Uruguay. The Program, undertaken during May 2003–January 2009, was implemented by the Organization of American States (OAS) under the supervision of the World Bank and with detailed advice from GW-MATE, and benefitted from the important contributions of the International Atomic Energy Agency (IAEA) and the BGR through German development cooperation. The scientific overview is followed by a detailed assessment of the main implications for resource management strategy, the progress of practical groundwater management and protection measures at local level through on-going pilot projects (both within and outside the GEF Program), and the status and strengthening of associated institutional and legal provisions. The ‘core reference document’ for this overview assessment is the GEF Program–Strategic Action Plan (Plan Estratégico de Acción/PEA) of 2009, but groundwater resource management dimensions are here the principal focus and their discussion is taken further. GW-MATE acknowledges the major contribution of the OAS Guarani Program Secretariat and Pilot Project Facilitators, together with that of national government agencies and committees, and of the consultants and academics executing various parts of the program under contract.