In the struggle to mitigate anthropogenic threats to environmental systems, science has made great progress identifying and quantifying the potential of various mitigation initiatives. It has made less progress in identifying and assessing how those initiatives will affect their targets and whether those initiatives can be adopted given the constraints of social, economic, and political systems. We present a framework for a science of mitigation that integrates understanding of mitigation potential with empirically based and context-specific knowledge from the social and behavioral sciences to address those gaps. The goal is to help change agents move beyond subjective judgment or broad theory toward a stronger basis for choosing and implementing mitigation strategies. This developing science incorporates knowledge about mitigation potential with knowledge about the plasticity of human responses to initiatives for change, feasibility of adopting and implementing such initiatives, and emerging principles for the effective design of initiatives. We place current and emerging lines of research within this framework and show how they can be developed to better inform practical mitigation choices, identify key research needs for this integrative science, and propose ways to support the needed efforts.