An exclusive human milk diet (EHMD) has been shown to reduce health complications of prematurity in infants born weighing ≤1250 g compared with cow milk-based diets. Accordingly, the number of available human milk (HM)-based nutritional products continues to increase. Newly available products, and those reportedly soon to enter the market, include homogenized donor HM and homogenized HM-based fortifiers. Existing literature demonstrating the benefits of an EHMD, however, is limited to non -homogenized HM-based products. Herein, we summarize existing evidence on the impact of homogenization on HM, with a particular focus on changes to the macromolecular structure of the milk fat globule and the subsequent impact on digestion kinetics. We use these published data to create a conceptual framework for the potential implications of homogenized HM-based nutritional products on preterm infant health. Importantly, we underscore that the safety and efficacy of homogenized HM-based products warrant investigation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)