Human milk is generally recognized as the gold standard in neonatal nutrition. The structure and composition of human milk are better mimicked in infant formulas that include cow s milk lipids and milk fat membrane extracts, which could also improve physiological properties. Nevertheless, very few infant formulas use cow' s milk lipids that are more expensive than vegetable lipids. The potential impact of milk lipid structure and composition on neonatal digestive hydrolysis, intestinal physiology, and gut microbiota was recently underlined by several scientific teams. In this context, the purpose of the present review was to summarize the specificity of composition and structure of human milk and to highlight the recent results on the modulation of infant formula interfacial composition and fat source on neonatal digestive hydrolysis, intestinal physiology, and gut microbiota. More specifically, the interfacial composition of model emulsions stabilized with milk polar lipids will be unraveled as well as the addition of apolar milk fat extracts in replacement to vegetable lipids in infant formulas. The impact of partially replacing vegetable lipids by milk lipids stabilized by milk fat membranes was investigated in the piglets. This replacement in fluenced the neonatal intestinal physiology through the release of immune- modulatory lipids, the modulation of proteolysis, and the modification of gut microbiota.Practical Applications:The potential development of infant formulas including cow’s milk lipid fractions with a structure closer to human milk is discussed. These more biomimetic formulas should result in enhanced nutritional bene fits concerning neonatal digestive hydrolysis, physiology, and gut microbiota development