The long-term goals of this scientific focus area (SFA) are to develop a flexible and extensible modeling framework that captures the dynamic multi-scale interactions among climate, energy, water, land, socioeconomics, critical infrastructure, and other sectors and to use this framework to study the vulnerability and resilience of coupled human and natural systems from local to continental scales under scenarios that include short-term shocks, long-term stresses, and feedbacks associated with human decision-making. It will also explore how different model configurations, levels of complexity, multi-model coupling strategies, and spatial and temporal resolutions influence simulation fidelity and the propagation of uncertainties. The first three years of the SFA will focus on systematically building the foundational scientific understanding and computational tools needed to develop and deploy an integrated multi-sector, multi-scale modeling framework, with an emphasis on the climate-energy-water-land nexus. Major research thrust areas include population dynamics, land use and land cover change, and a “deep dive” into energy-water interactions in the western United States. Our approach emphasizes leveraging existing efforts and emerging capabilities, systematically increasing complexity, and engaging with a range of communities to help establish this SFA as a long-term home for cutting-edge climate impact, adaptation, and vulnerability research. Ultimately, our goal is to dramatically improve scientific understanding of how the complex coupled human-Earth system responds to different stresses, which will in turn inform decision-making across a range of sectors and scales.