Environmental problems caused by human activities are increasing; biodiversity is disappearing at an unprecedented rate, soils are being irreversibly damaged, freshwater is increasingly in short supply, and the climate is changing. To reverse or even to reduce these trends will require a radical transformation in the relationship between humans and the natural environment. Just how this can be achieved within, at most, a few decades is unknown, but it is clear that academia must play a crucial role. Many believe, however, that academic institutions need to become more effective in helping societies move toward sustainability. We first synthesize current thinking about this crisis of research effectiveness. We argue that those involved in producing knowledge to solve societal problems face three particular challenges: the complexity of real-world sustainability problems, maintaining impartiality when expert knowledge is used in decision making, and ensuring the salience of the scientific knowledge for decision makers. We discuss three strategies to meet these challenges: conducting research in interdisciplinary teams, forming research partnerships with actors and experts from outside academia, and framing research questions with the aim of solving specific problems (problem orientation). However, we argue that implementing these strategies within academia will require both cultural and institutional change. We then use concepts from transition management to suggest how academic institutions can make the necessary changes. At the level of system optimization, we call for: quality criteria, career incentives, and funding schemes that reward not only disciplinary excellence but also achievements in inter-/transdisciplinary work; professional services and training through specialized centers that facilitate problem-oriented research and reciprocal knowledge exchange with society; and the integration of sustainability and inter-/transdisciplinary research practices into all teaching curricula. At the level of system innovation, we propose radical changes in institutional structures, research and career incentives, teaching programs, and research partnerships. We see much value in a view of change that emphasizes the complementarity of system innovation and system optimization. The goal must be a process of change that preserves the traditional strengths of academic research, with its emphasis on disciplinary excellence and scientific rigor, while ensuring that institutional environments and the skills, worldviews, and experiences of the involved actors adapt to the rapidly changing needs of society.