The natural environment is constantly changing due to both natural variability and anthropogenic forcing, and human activities are similarly evolving over time in response to a wide range of processes and constraints. Understanding the co-evolution of human and natural systems across a range of spatial and temporal scales is one of the preeminent scientific challenges of our time, and demands a multifaceted approach that accounts for processes and interactions across wide range of spatial and temporal scales. To address this challenge, a multi-institutional team led by Pacific Northwest National Laboratory has launched the Integrated Multi-scale, Multi-sector Modeling (IM3) project, sponsored by the US Department of Energy. We are developing a flexible and extensible modeling framework to capture the dynamic multi-scale interactions among energy, water, land, climate, socioeconomics, critical infrastructure, and other sectors, with an initial focus on population dynamics, land use and land cover change, and the energy-water nexus. The focus of our model development and numerical experiments is one evaluating the resilience of coupled human and natural systems to both short-term shocks and long-term stresses, and also exploring how different resolutions, configurations, levels of complexity, and model coupling strategies influence simulation fidelity and uncertainty propagation. This presentation will focus on recent results and lessons learned from activities across the IM3 project, as well as new emerging directions and the potential for broadening collaborations with other projects and teams.