The interaction between nutrition and infection was the subject of important work by several groups in the 1960s. The explosion of knowledge in immunology, including innate immunity, has led to increased understanding of the impact of nutrition on host defence, but much more work needs to be done in this area. In the last decade an increasing volume of work has opened up the previously obscure world of human endogenous flora. This work suggests that the microbiome, the total genetic pool of the microbiota, contributes to the already complex interaction between nutrition and infectious disease. The established concept that nutritional status, host defence and infection all impact on each other now has to be expanded into a multiple interaction, with the microbiota interacting with all three other elements. There is good evidence that the microbiome programmes host defence and drives a metabolome that impacts on energy balance, and indeed on some micronutrients. In turn, host defence shapes the microbiome, and nutritional status, particularly micronutrient status, helps determine several elements of host defence. While interventions in this area are in their infancy, the understanding of interactions that already have an enormous impact on global health is now at a threshold. The present review explores the evidence for these interactions with a view to putting potential interventions into the context of a conceptual framework.