The promotion of nutritional strategies that optimize natural defence mechanisms in fish is of critical importance in producing robust juveniles and adult fish. These animals are more capable of minimizing the impact of opportunistic pathogen attack, thus improving liveability and performance characteristics. The importance of the piscine gastrointestinal tract as a major endocrine and osmoregulatory organ is well reported as is its function as a defensive barrier to pathogen attack. Investigations using the inclusion of a specific structural form of mannan oligosaccharide have been shown to improve the performance parameters, immune status, and gut morphology and improve an important aspect of barrier protection through the enhancement of mucal production in a number of aquaculture species. The selenium status of an animal is pivotal in determining the success of the innate and adaptive immune response of the animal, and the use of an organic selenium source, in the form of a selenoyeast, has been shown to improve enzyme function and tissue uptake. The antioxidant role of many of the selenoptroteins and the role of selenium in the glutathione peroxidase enzyme pathways involved in the control of oxidative stress is critical if oxidative damage and cell membrane lipid peroxidation are to be prevented. The use of these compounds as feed additives has important implications for health management in commercial aquaculture facilities. Further research is needed to evaluate the benefits offered by a range of commercial products.