Recent demonstrations link clinical conditions, phenotypes alternating from inflammatory bowel disease, obesity, and allergic diseases to neurodevelopmental disorders, to aberrant gut microbiota composition. This has led to a growing interest in host-microbe crosstalk, characterizing the healthy microbiome and modifying its deviations at an early age. The rationale arises from the recognition of the intimate interrelationship between diet, immune system, and microbiome and the origins of human diseases. Before satisfactory preventive measures can be put in practice, important questions remain to be solved. First, we need more profound understanding of the complex mechanisms underlying these heterogeneous manifestations of immune-mediated and microbiome-associated chronic conditions. Second, long-term follow-up studies are required to determine whether the changes in the microbiome underlie the pathogenesis of noncommunicable diseases or are merely end results thereof, confronting the question of causality. This uncertainty notwithstanding, the complex and bidirectional interrelationship of the diet and the gut microbiota is becoming evident. Early exposures by the enteral route induce dynamic adaptive modifications in the microbiota composition and activity, which may carry long-term clinical impacts. Microbiota changes, again, control energy acquisition and storage and may contribute to gut immunological milieu; high-energy Western diets alter the microenvironment of the gut leading to propagation of the inflammatory tone and perturbation of gut barrier function and thereby to systemic low-grade inflammation. On this basis, rigorous clinical intervention studies, providing the ultimate answers to these questions, need accurate characterization of the immediate environment of the child, in particular the early nutrition. The model of early nutrition for future studies is the healthy breastfed infant that remains healthy in the long term. Scientific interest is currently extending from the duration of breastfeeding to the composition of breast milk, which shows marked variation according to the mother's immunological and metabolic health, antibiotic use, and mode of delivery. Human milk, rich in bioactive compounds, including health-promoting microbes and their optimal growth factors, human milk oligosaccharides, continues to afford tools to study diet-microbiota interactions for research aiming at reducing the risk of noncommunicable diseases.