During the transition from late gestation to early lactation, homeorhetic adaptations allow dairy cows to produce copious amounts of milk without compromising their own health. This transition, however, remains a potentially perilous time for dairy cows as it is associated with a high risk of infectious and metabolic disorders. These conditions have a negative impact on the dairy industry because they contribute to economic losses and compromise animal welfare. Despite decades of research dedicated to advancing knowledge and aiding in the prevention of periparturient disorders, their incidences remain unacceptably high. Thus, novel treatment options are required. This dissertation research was undertaken to evaluate a novel therapy to improve health and production in Holstein cows. A series of studies was conducted to: i) Evaluate the effect of recombinant bovine interleukin-8 (rbIL-8) on uterine health and milk production, ii) Evaluate the effect of rbIL-8 treatment on insulin resistance in Holstein calves, iii) Evaluate the effect of rbIL-8 treatment on dry matter intake and orchestrated homeorhetic changes that prioritize milk production in Holstein cows, iv) Evaluate associations between periparturient plasma insulin concentration and milk production of Holstein cows, and v) Evaluate the effects of treating Holstein cows with pegylated recombinant bovine granulocyte colony stimulating factor (rbG-CSF) on periparturient diseases, milk production, and reproductive performance. Chapter 2 describes two studies evaluating the effects of rbIL-8 administered via intrauterine (IU) infusion shortly after parturition on uterine health, lactation performance, and blood metabolites. Recombinant bIL8-IU treatment was effective in preventing puerperal metritis in multiparous cows, reducing the incidence of postpartum hyperketonemia (HYK), and increasing milk production in the long-term. Chapter 3 describes the effect of systemic administration of rbIL-8 to Holstein calves on peripheral tissue insulin sensitivity. Recombinant bIL-8 induced insulin resistance accompanied by systemic inflammation and caused alterations to blood metabolites and white blood cell populations. In Chapter 4 we evaluated whether recombinant bovine interleukin-8 treatment administered intrauterine or intravenously within 12 h of parturition would increase milk production through effects on insulin resistance, dry matter intake, and/or by altering metabolism. Findings from Chapter 4 reinforce our findings on increased milk production following rbIL-8-IU treatment. Intrauterine administration of rbIL-8 increased dry matter intake and did not alter metabolism. Treatment with rbIL-8-IU reduced the incidence of HYK and improved cow overall health during the postpartum period. In Chapter 5, we assessed the association between plasma insulin concentration around parturition and milk yield. Chapter 5 highlights the importance of suppression of postpartum insulin secretion as a key endocrine adaptation to support high milk production. Chapter 6 describes a study evaluating the effects of treating Holstein cows with rbG-CSF on periparturient diseases, milk production, and reproductive performance. Although rbG-CSF treatment increased circulating white blood cell counts, it was ineffective in improving health and reproduction. In fact, the incidence of lameness and combined disease morbidity was increased for cows treated with rbG-CSF. In summary, this dissertation provides new insights into a novel therapy to improve health and lactation performance in Holstein cows. We conclude that IU administration of rbIL-8 shortly after parturition is an effective therapy to improve heath and lactation performance in lactating cows. More studies are needed to elucidate the exact mechanism by which rbIL8-IU treatment increases dry matter intake. We do not support the use of rbG-CSF treatment to prevent periparturient diseases in Holstein cows. Further research is needed to confirm the negative effects of rbG-CSF treatment on postpartum lameness.