Various scientists and philosophers have heavily criticized what they see as problematic forms of ‘nutritional reductionism’ or ‘nutritionism’ whereby studying food–health interactions at the level of isolated food components produces largely misguided science and misleading interpretations. However, the exact target of these diverse criticisms remains elusive, and its implications are overstated, which may hinder scientific understanding. To better identify the types of flaws supposedly hindering reductionist research, we disentangle three types of reductionist claims to better determine what the debate is (...) about and to propose ways to move it forward. We then present a qualified defence of the reductionist programme that hinges on the ability to identify nutritional causes that make a difference, which we illustrate through central examples in the history of nutrition. This defence is taken further by using insights from the philosophy of mechanisms to analyse how the field of nutritional ecology offers a synthetic framework to explain, generate, and test predictions about nutrient–organism interactions, which is premised on the biological mechanisms of nutrient-specific appetite regulation. The result, which we call ‘synthetic reductionism’, avoids many, though perhaps not all, of the challenges raised by anti-reductionists, and also highlights the potential of reductionism to identify nutritional difference makers. (shrink)