The Millennium Ecosystem Assessment (MA) introduced a new framework for analyzing social-ecological systems that has had wide influence in the policy and scientific communities. Studies after the MA are taking up new challenges in the basic science needed to assess, project, and manage flows of ecosystem services and effects on human well-being. Yet, our ability to draw general conclusions remains limited by focus on discipline-bound sectors of the full social-ecological system. At the same time, some polices and practices intended to improve ecosystem services and human well-being are based on untested assumptions and sparse information. The people who are affected and those who provide resources are increasingly asking for evidence that interventions improve ecosystem services and human well-being. New research is needed that considers the full ensemble of processes and feedbacks, for a range of biophysical and social systems, to better understand and manage the dynamics of the relationship between humans and the ecosystems on which they rely. Such research will expand the capacity to address fundamental questions about complex social-ecological systems while evaluating assumptions of policies and practices intended to advance human well-being through improved ecosystem services.