The transition from late gestation to early lactation results in dramatic physiological changes including metabolic changes and immunosuppression in the dairy cow. As a result, cows are at a high risk for disease during this time. Evidence supporting a link between metabolic status and naturally occurring immunosuppression is growing. This review focuses on the impacts of metabolic status, and the metabolites that characterize it, on the immune response of cows during the transition period. Glucose is the preferred fuel for immune cells and its low concentration during the transition period may partly explain the naturally occurring immunosuppression at this time. To our knowledge, ketones are not utilized by immune cells and primarily have been shown to inhibit the immune response when concentration is relatively high. The effect of fatty acids on the immune system response remains unclear. Evidence suggests that the type of fatty acid can either stimulate (i.e. saturated fatty acids) or inhibit (i.e. unsaturated fatty acids) the immune response. We have suggested that an index for physiological imbalance (PI), based on circulating metabolites that characterize metabolic status, directly relates to mechanisms associated with the development of disease and is superior to calculated energy balance and therefore is a better predictor of risk of disease. The usefulness of the PI index as a predictor of risk of disease and the mechanisms associated with the links between degree of PI and immunosuppression for dairy cows during the transition period warrants further investigation.