The immune system is composed of integrated, genetically and environmentally regulated sets of cells and molecules that control the response to external and internal stimuli, including pathogenic microorganisms. In terms of infectious organisms, the response of the host largely reflects the relationship or adaptation between the host and agent. The variation in host response is influenced through genotype by environment interactions. Epigenetic effects are also highly sensitive to environmental influence and thus can rapidly alter individual phenotype. These are non-sequence alterations to DNA that cause changes in DNA structure that affect its availability for transcription. Consequently, disease is largely the product of incompatible gene by environmental interactions that include both genetic and epigenetic effects. These interactions vary at both the individual and population level. It is therefore particularly relevant to understand host-pathogen relationships and adaptations under various stress and management conditions. Improved understanding of the biology and genetic relationships between the host and pathogen, particularly those that affect the immune system during periods of production stress, should facilitate implementation of non-traditional approaches to improve the health of intensively reared livestock. This paper will briefly describe some of the genetic and environmental variation documented in immune response and performance traits of pigs, mainly using examples from experiments performed by the authors over the last two decades of research. Integrating quantitative and molecular genetic strategies to enhance the immune performance and improve inherent disease resistance of pigs, as well as other livestock species, has been the focus of much research. The data collected demonstrates that considerable phenotypic variation exists in immune response traits of pigs and that a substantial portion of that variation is due to additive genetic variance allowing for selective breeding of pigs with higher immune responsiveness. The underlying principle being that optimal disease resistance should be a function of optimal resistance-mediating defense mechanisms. Genes that underlie high or low immune responses and disease resistance are beginning to be understood, such as those within the MHC; however, selective breeding for complex disease traits should still be based on estimated breeding values of superior heritable phenotypes. The next step will be to evaluate high and low immune responsiveness and it’s influence on health and production traits in several commercial breeding nucleus herds.