While the primary purpose of food is to provide nutrition and a source of macro and micronutrients, secondary natural products are important in the differentiation between foods including taste, flavour, protection of the host species, additional health benefits for consumers and response to biotic and abiotic stress. Much of the non-pharmacological emphasis on secondary natural products in foods has focused on the removal of anti-nutritive components such as phytates, glucosinolates, saponins, cyanogenic glycosides and others. Optimisation of beneficial secondary natural products has been comparatively little studied since the starting point of optimisation of intake levels has been difficult to define or achieve. Secondary natural products are important in both health and disease—even though methods to determine how individual components (and mixtures of compounds) act on whole organisms. Part of the challenge is that secondary natural products have a different value from the perspective of the producing and the consuming species and this conflict lies at the core of how they are investigated. The classification of quorum sensing molecules as being members of the class of semiochemicals is important both from an organisational standpoint and as a way of thinking about them. Optimisation of levels of secondary natural products will require a redefining of what ‘optimal’ means and a better understanding of complex living systems and mixtures of compounds. Current paradigms designed to investigate the relevance and importance of food and food system derived secondary natural products have identified some of the challenges but appear to be failing to provide coherent solutions. This does not mean that the identified challenges are insoluble but perhaps the traditional reductionist, isolative and synthetic approaches are inappropriate.