In South America, water is at its heart, underpinning hydropower generation, agricultural production, and industry. Transboundary water bodies cover almost half of South America territory. All countries in the region share transboundary waters, such as aquifers, basins, and rivers that may create enough reason for political conflict among those countries. Therefore, there is a vital need to develop regional strategies to manage those shared water resources, especially with the continuous increase in population growth, climate change, and the increase in demand for water. This chapter takes the La Plata basin and the Guarani Aquifer in South America as a representative example to discuss the management of transboundary water bodies situation and demonstrates how the countries are collaborating to face the challenge to achieve sustainable development on both sides of their borders.