Weaning is a multifaceted stressor and may involve numerous husbandry practices, including the abrupt separation of the calf from its dam, a nutritional adjustment to a non-milk diet and social reorganisation and, additionally, is often associated with other husbandry practices, such as housing and transport. Stress-induced disease susceptibility in livestock animals has documented economic and societal consequences and the sense of urgency to understand and intervene in these is becoming increasingly important. Available published research has examined the physiological and behavioural responses to weaning stress in calves, but no study has yet characterised the molecular response. This Ph.D. project aimed to obtain a greater understanding of the impacts of weaning on both the molecular and physiological responses in order to elucidate the immune mechanisms responsible for stress dependent immune suppression in calves post weaning. A series of studies were conducted to investigate i) the effect of weaning stress as an accumulative stressor on haematological and immunological variables to assess whether combining weaning with housing elicits a greater response than housing alone, ii) to (a) characterise, in male and female calves habituated to housing, the immune response to weaning stress at the physiological and molecular levels, and (b) assess the difference between calves weaned and housed in the presence of the dam and those weaned and housed away from the dam, and iii) the effect of accumulative stressors on the global transcriptomic response in blood leukocytes to weaning stress. The results of this thesis demonstrate that stress can have accumulative effects and by combining housing with weaning, an increase in neutrophil number and decrease in lymphocyte number was found. Concerning management at weaning, it is evident that calves, particularly intact male calves, may benefit from a weaning strategy where the calves are allowed contact with the dam but prevented from suckling for a number of days before total separation occurs. Weaning calves away from the dam also resulted in a much stronger stress response, resulting in an increase in the expression of inflammatory cytokines, the glucocorticoid receptor, TLR4, CD62L and Fas, than weaning calves next to the dam. Additionally, a far more potent inflammatory response, at the transcriptomic level, was reported to occur in weaned and housed calves compared with housed calves, indicating that stress activates the innate immune system to increase surveillance. An important finding of this thesis was that simultaneously weaning and housing of calves produces a perturbation to the homeostasis of the leukocyte transcriptome which was still present 7 days following weaning. Thus the identification of novel biomarkers and regulatory gene networks that are stress activated provides a mechanistic framework to characterise the multifaceted nature of weaning stress adaptation in beef calves.