Differences in the composition and structure of lipid droplets in infant formula (IF) and human milk (HM) can affect the fat digestion of infants, leading to high risk of metabolic diseases during later stages of growth. Recently, interest in simulating HM fat (HMF) has gradually increased due to its beneficial functions for infants. Much research focuses on the simulation of fatty acids and triacylglycerols. Enzymatic combined with new technologies such as carbodiimide coupling immobilization enzymes, solvent-free synthesis, and microbial fermentation can improve the yield of simulated HMF. Furthermore, fat modification in next-generation IF requires attention to the impact on the structure and function of milk fat globules (MFG). This review also summarizes the latest reports on MFG structure simulation, mainly related to the addition method and sequence of membrane components, and other milk processing steps. Although some of the simulated HMF technologies and products have been applied to currently commercially available IF, the cost is still high. Furthermore, understanding the fat decomposition of simulated HMF during digestion and assessing its nutritional effects on infants later in life is also a huge challenge. New process development and more clinical studies are needed to construct and evaluate simulated HMF in the future.