As the nation’s economic activities, security concerns, and stewardship of natural resources become increasingly complex and globally interrelated, they become ever more sensitive to adverse impacts from weather, climate, and other natural phenomena. For several decades, forecasts with lead times of a few days for weather and other environmental phenomena have yielded valuable information to improve decision-making across all sectors of society. Developing the capability to forecast environmental conditions and disruptive events several weeks and months in advance could dramatically increase the value and benefit of environmental predictions, saving lives, protecting property, increasing economic vitality, protecting the environment, and informing policy choices. Over the past decade, the ability to forecast weather and climate conditions on subseasonal to seasonal (S2S) timescales, i.e., two to fifty-two weeks in advance, has improved substantially. Although significant progress has been made, much work remains to make S2S predictions skillful enough, as well as optimally tailored and communicated, to enable widespread use. Next Generation Earth System Predictions presents a ten-year U.S. research agenda that increases the nation’s S2S research and modeling capability, advances S2S forecasting, and aids in decision making at medium and extended lead times.