With the changes in climatic, biophysical, socio-cultural, economic, and technological components, paradigm shifts in natural resources management are unavoidably and have to be adapted/modified to harmonize with the global changes and the local communities’ needs. This chapter focuses on sustainable land use and watershed management in response to climate change impacts. The first part covers some definitions and background on sustainable land use, watershed management approach, and sustainable watershed management. The second part describes the use of the Geographic Information System (GIS) and Spatial Decision Support System (SDSS) model focusing on the framework for a planning and decision making, computer-based system for supporting spatial decisions. The mathematical programming has been reviewed focusing on optimization algorithms that include optimization modeling and simulation modeling for decision making. Finally, the example of methodology development for sustainable land use and watershed management in response to climate change in Dong Nai watershed, Vietnam is presented.