In this study, we explore how the US Environmental Protection Agency (EPA) uses science in its overseeing of genetically modified (GM) plants producing their own pesticides (plant-incorporated protectants or PIPs). Our analysis is based on a systematic review of EPA's product assessments, regulatory decisions and policy documents on GM plants. In regulating PIPs, product characteristics remain the fundamental basis for the agency's risk assessment. However, a recent ruling by the EPA represents a departure from a strict 'product' approach to risk assessment. By considering not only product characteristics, but also the process by which a GM crop was developed, the EPA may be seen as adopting a cautionary approach under conditions where current science is unable to resolve whether GM crops and foods impose unique risks by comparison with products derived through conventional breeding. The EPA's case-by-case evaluations of GM products rely heavily on models and indirect measurements interpreted through biological and biochemical principles.