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It is urgent in science and society to address climate change and other sustainability challenges such as biodiversity loss, deforestation, depletion of marine fish stocks, global ill-health, land degradation, land use change and water scarcity. Sustainability science (SS) is an attempt to bridge the natural and social sciences for seeking creative solutions to these complex challenges. In this article, we propose a research agenda that advances the methodological and theoretical understanding of what SS can be, how it can be pursued and what it can contribute. The key focus is on knowledge structuring. For that purpose, we designed a generic research platform organised as a three-dimensional matrix comprising three components: core themes (scientific understanding, sustainability goals, sustainability pathways); cross-cutting critical and problem-solving approaches; and any combination of the sustainability challenges above. As an example, we insert four sustainability challenges into the matrix (biodiversity loss, climate change, land use changes, water scarcity). Based on the matrix with the four challenges, we discuss three issues for advancing theory and methodology in SS: how new synergies across natural and social sciences can be created; how integrated theories for understanding and responding to complex sustainability issues can be developed; and how theories and concepts in economics, gender studies, geography, political science and sociology can be applied in SS. The generic research platform serves to structure and create new knowledge in SS and is a tool for exploring any set of sustainability challenges. The combined critical and problem-solving approach is essential.