Although scientists and policymakers frequently see genetically modified (GM) crops as part of the solution to the global ‘grand challenge’ of agricultural sustainability, all too commonly they have been viewed as part of the problem. They have been met with resistance by a variety of social actors, their regulation has been challenged as inadequate, even biased, and their consumption recurrently rejected by consumers as not delivering a societal benefit. In this chapter I examine the case of GM crops and how an analysis of the controversy investigated through the lens of responsible innovation can cast light on the conditions under which innovations in the agricultural sciences can become responsive to this important global challenge. First, I set out a brief context to GM crops within the grand challenge of agricultural sustainability. Second, I examine empirical research on the socio-political impacts of GM crops in Brazil, India and Mexico, exploring the views of farmers, scientists and publics. Third, in response to the clear absence of authoritative governance that is identified across these three diverse geopolitical contexts, I explore the potential of frameworks of responsible innovation to reconfigure the debate on the governance of GM foods and crops, and to provide new pathways to move it away from its current polemic and impasse. I conclude with a modest set of recommendations.