The immune system is genetically wired to elicit robust protective responses to infectious organisms and individuals with an appropriately balanced immune response have health advantages. The High Immune Response (HIR) technology classifies cows as High (H), Average (A) and Low (L) immune responders (IR) based on their estimated breeding values (EBV) for antibody-mediated (AMIR) and cell-mediated (CMIR) immune response. Two previous studies by our group; nationwide Canadian study and another a large US dairy, were the first to demonstrate that H responders have a lower occurrence of postpartum related illness and thus require less therapeutic intervention. Notably, several studies show that HIR cows produce colostrum and milk of superior quality; naturally enriched with high concentrations of host-defense related molecules. Specifically, cows classified as H AMIR have greater concentrations of serum antigen or vaccine-induced specific antibodies, total immunoglobulin (Ig), and natural antibodies of both IgM and IgG isotypes, and innate defense molecules in the milk such as β-lactoglobulin. These bioactive molecules provide enhanced passive immunity to newborn calves and improved disease resistance of the mammary gland both during lactation and the dry period. In addition, our group is among the first to show that colostrum and milk exosomes contain unique miRNA profiles. Critical immune-related miRNA are differentially expressed with greater expression observed in colostrum from HIR cows. Exogenous uptake of colostrum and milk exosomes containing miRNA from H responders by human intestinal epithelial cells enhances cell viability and suggests their bioavailability to humans and a potential immunoregulatory role in gut health. Advanced understanding of the interplay between the genome and the epigenome and the environment is expected to open the door for new applications of the HIR technology. Identification of genomic and epigenetic biomarkers for enhanced herd health will add to the growing list of traits that allow the dairy industry to select superior breeding stock. Natural value-added colostrum and milk will benefit mammary gland health, and humans consuming these healthful dairy products.