When intense public controversy erupted around agricultural biotechnology in the late 1990s, critics found opportunities to challenge risk assessment criteria and test methods for genetically modified (GM) products. In relation to GM food, they criticized the concept of substantial equivalence, which European Union and United States regulators had adopted as the basis for a harmonized, science-based approach to risk assessment. Competing policy agendas framed scientific uncertainty in different ways. Substantial equivalence was contested and eventually recast to accommodate some criticisms. To explain how the concept changed, this article links two analytical perspectives. Regulatory-science perspectives illuminate how the scientification of politics and politicization of science led to shifts in the boundary between science and policy. Governance perspectives illuminate how the collective problem for policy was redefined to provide a new common ground for some stakeholders. Overall, substantial equivalence was recast to govern the social conflict and address legitimacy problems of regulatory procedures.