Abstract: Groundwater is both an invaluable and a vulnerable resource. Aquifer resources management, aiming at the responsible exploitation and adequate protection of the groundwater resources, is therefore of key importance and has to be based on sound hydrological, environmental, economic and social principles. Aquifer-wide groundwater projects are carried out to collect the required area-specific information, to understand ongoing processes, to identify the management issues to be addressed and to develop an adequate management strategy and action plan. The quality of the project results depends to a large extent on the science and methodologies adopted in the design and used during the implementation of the projects. In this context, a project was carried out recently to analyse the scientific aspects of—among others—the transboundary aquifer projects within the IW: Portfolio of the Global Environmental Facility (GEF) and to make recommendations for scientific strengthening and innovation. This paper presents the main outcomes of this analysis. In order to accomplish groundwater resources management goals in the case of transboundary aquifers, a balanced joint strategy is needed. Analysis of documentation on completed and on-going transboundary aquifer projects has shown a wide range of scientific activities that contribute positively to the development of such strategies. This analysis has also identified options for increasing the positive impacts of science on strategy development; some of these options have been pioneered already and deserve wider application other ones are relatively new. Important options are: integrating transboundary aquifer resource management in a wider environmental–socio-economical context (holistic approach); exploring causal chains to better understand the processes of change of groundwater resources; using this improved understanding for optimising groundwater assessment and monitoring programmes; and adaptive management. In addition, to obtain maximum benefit of the scientific results there is a general need to promote effective communication at all levels, between the scientific community and policy-/decision makers, as well as with the local community who have a major role to play in the use and conservation of the resources. All of this should be accompanied by the harmonisation of the legal instruments and co-operation agreements between countries and the communities involved. Two case studies, one in South America and one in Southern Africa, are added as examples of the setting and approach of the analysed transboundary aquifer projects.