This dissertation reviews the progress in climate, land, energy and water (CLEW) multi-scale models and proposes a framework for quantitative assessment of multi-sector long-term policies. The so-called CLEW nexus approaches have shown their usefulness in assessing strategies to achieve the Sustainable Development Goals in the contexts of increasing demands, resource scarcity, and climate change. This thesis contributes to existing research by (1) focusing on the palette of feasible long-term sustainable solutions at different scales to face current and future sustainable development challenges;​ (2) improving understanding of how CLEW models can best advise on sustainable development research and highlighting the strengths and limitations of existing configurations;​ (3) inquiring what is needed for new tools to be accessible, transferable and successful in informing the final user. This dissertation first reviews a set of models that can meet the needs of decision makers discussing research gaps and critical needs and opportunities for further model development from a scientific viewpoint. Particular attention is given to model accessibility, usability, and community support. The review explores at different scales where and why some nexus interactions are most relevant, finding, for example, that both very small scale and global models tend to neglect some CLEW interactions. This dissertation also presents the Nexus Solutions Tool (NEST):​ a new open modeling platform that integrates multi-scale energy-water-land resource optimization with distributed hydrological modeling. The new approach provides insights into the vulnerability of water, energy and land resources to future socioeconomic and climatic change and how multi-sectoral policies, technological solutions and investments can improve the resilience and sustainability of transformation pathways while avoiding counterproductive interactions among sectors. Finally, a case study analysis of the Indus River Basin in South Asia demonstrates the capability of the NEST framework to capture important interlinkages across system transformation pathways towards the United Nations' Sustainable Development Goals. The results show how the Indus countries could lower costs for development and reduce soil pollution and water stress, by cooperating on water resources, electricity and food production.