Sustainable animal health is one of the key objectives in modern livestock management, as animal health is also directly linked to performance and feed efficiency. The feed industry, however, faces an increasing number of uncertainties associated with declining resources, climate change and increasing world market prices for feed materials. Specialized feed ingredients and feed additives can promote feed utilization and animal health by increasing the resilience to infectious disease thereby meeting also societal demands to reduce the need for an undesirable use of antibiotics in the absence of severe infectious diseases. Feed additives are commonly originating from natural substances such as organic acids, pre- and probiotics and are already widely accepted and used. Understanding their mechanism of action on pathogen exclusion and improvement of gut health, are the drivers for the development of new additives, including phytogenic agents, which are added due to their multiple actions as antimicrobials, antioxidants and digestives and measurable beneficial effect on the innate immune system. Such innovative solutions require a multi-disciplinary cooperation with the aim to understand the specific mode of action on digestive functions, the gut microbiome and the cross-talk between the intestinal mucosal barrier and other mucosal organs such as the lungs and the innate immune system. Moreover, specific pharmaceutical technologies are needed for a targeted release of feed additives within the intestinal tract and to guarantee their stability during feed and drinking water application. Bridging these insights with the physiological development of animals at different stages of life and the unavoidable risk for endogenous and environmental stressors, enables a cost-effective integration of natural feed additives into sustainable health programs of livestock operations, ultimately contributing also to animal wellbeing and food safety and security.