The identification of nutrients and the study of their bioactivity were significant developments in the evolution of contemporary nutrition science. This review argues for shifting the focus towards food in order to better understand the nutrition-health interface. It begins by introducing the concept of food synergy (a perspective that more information can be obtained by looking at foods than at single food components) to denote the action of the food matrix (the composite of naturally occurring food components) on human biological systems. A proposal is then made for the means by which food-focused research might build the knowledge base for etiologic discovery and appropriate dietary advice. The diet-heart disease dilemma is put forward as an example of where a nutrient-based approach has limitations, and a summary of studies targeting food composition strengthens the case for a food-based approach. Finally, the argument is made that evidence from interventions points back to the central position of food in the relationship between nutrition and health, a position that begs for more whole food-based research.