The structure, status, and processes of the groundwater system, which can only be acquired through scientific research efforts, are critical aspects of water resource management. Isotope hydrology and hydrogeology is a genuinely interdisciplinary science. It developed from the application of methods evolved in physics (analytical techniques) to problems of Earth and the environmental sciences since around the 1950s. In this regard, starting from hydrogeochemical data, stable and radioactive isotope data provide essential tools in support of water resource management. The inventory of stable isotopes, which has significant implications for water resources management, has grown in recent years. Methodologies based on the use of isotopes in a full spectrum of hydrological problems encountered in water resource assessment, development, and management activities are already scientifically established and are an integral part of many water resource investigations and environmental studies. The driving force behind this Special Issue was the need to point the hydrological and water resource management societies in the direction of up-to-date research and best practices.