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Global climate change creates critical challenges with increasing temperature, reducing snowpack, and changing precipitation for water, energy, and food, as well as ecosystem processes at regional scales. Ecosystem services provide life support, goods, and natural resources from water, energy, and food, as well as the environments. There are knowledge gaps from the lack of conceptual framework and practices to interlink major climate change drivers of water resources with water-energy-food nexus and related ecosystem processes. This paper provided an overview of research background, developed a conceptual framework to bridge these knowledge gaps, summarized California case studies for practices in cross sector ecosystem services, and identified future research needs. In this conceptual framework, climate change drivers of changing temperature, snowpack, and precipitation are interlinked with life cycles in water, energy, food, and related key elements in ecosystem processes. Case studies in California indicated climate change affected variation in increasing temperature and changing hydrology at the regional scales. A large variation in average energy intensity values was also estimated from ground water and federal, state, and local water supplies both within each hydrological region and among the ten hydrological regions in California. The increased regional temperature, changes in snowpack and precipitation, and increased water stresses from drought can reduce ecosystem services and affect the water and energy nexus and agricultural food production, as well as fish and wildlife habitats in the Sacramento-San Joaquin Delta (Delta) and Central Valley watersheds. Regional decisions and practices in integrated management of water, energy, food, and related ecosystem processes are essential to adapt and mitigate global climate change impacts at the regional scales. Science and policy support for interdisciplinary research are critical to develop the database and tools for comprehensive analysis to fill knowledge gaps and address ecosystem service complexity, the related natural resource investment, and integrated planning needs.