Holstein steers contribute significantly to US beef production. Healthy feeder calves are more efficient and produce carcasses with greater value. Holsteins have the genetic capability to produce carcasses with comparable quality to many common beef breeds, but there are unique challenges to feeding Holsteins. Genetic differences between Holsteins and common beef breeds influence health. Additionally, early life management and other environmental factors can have long-term effects on the health and productivity of Holstein feeder calves. Holstein heifers had greater inflammatory responses than Angus heifers when evaluated in both ex vivo fibroblast and in vivo lipopolysaccharide challenge models. In both models, the Holstein heifers produced approximately 3 times more inflammatory mediators than the Angus heifers. The greater inflammatory capacity is likely due to a combination of genetic and epigenetic factors. In fact, pre-weaning nutrition influenced the risk of morbidity and mortality to a combined bovine herpesvirus-1 and Mannheimia haemolytica respiratory disease challenge in Holstein calves a month after weaning. Calves fed a restricted quantity of milk replacer, a common management strategy, had greater (P ≤ 0.05) mortality (4/15) compared with calves fed 2.5 times more milk replacer (0/15). In agreement, the restricted fed calves had greater measures of systemic inflammation, increased peripheral blood neutrophil:lymphocyte ratio and plasma haptoglobin concentrations. In contrast, many management strategies that are common among Holstein calves improve their health in a feed yard. These management strategies include: vaccination (viral and bacterial antigens), weaning, castration, dehorning, and feed bunk and water trough training. Implementing these management strategies to calves will reduce stress and its negative effects on immunity during arrival at the feed yard. Taken together, management decisions of Holsteins during the calf phase are important as they can have either positive or negative effects on future health.