Background: Infant formula (IF) requires further optimization as there are still differences in health consequences between human milk (HM) and IF. Scope and approach: The present review addresses the challenges and future opportunities inherent in the production of more biomimetic and sustainable IF. After presenting the targets, limitations and challenges for IF optimization, process innovations that could contribute to designing the next-generation of IF are discussed. The final section describes how such improvements should be addressed by means of a more systemic approach. Key findings and conclusions: Gaps in our knowledge of the compounds and structures in HM and their effects on digestion and health still exist, rendering the biomimicry of HM more difficult. Overall, optimizing IF is complex and requires trade-offs between synergistic and conflicting objectives, which include HM biomimicry, safety, functionality, ingredient sourcing as well as environmental, economic and social sustainability issues. Process innovations and optimized technological routes, including minimal processing, offer opportunities to implement new ingredients and improve the preservation of IF compounds, while ensuring microbial safety and addressing several pillars of sustainability through energy costs or reductions in gas emissions. Given the complexity of producing biomimetic and sustainable IF, a multi-objective optimization strategy is proposed, reliant on a multidisciplinary approach, where nutrition and process engineering would play pivotal roles with assistance from other disciplinaries such as biochemistry, microbiology, pediatric medicine, data and consumer sciences and public health. This rethinking of IF production should be driven by a multidisciplinary, non-profit consortium involving the entire value chain.