A large body of work has been conducted to elucidate the link between the loss of viability, sensitivity to pro-inflammatory mediators and the impairment of antimicrobial functions affecting the innate immune cells, the occurrence of uncontrolled inflammations, and the sudden alteration of the metabolism during the transition from pregnancy to lactation in highproducing dairy cows. Despite this massive effort, a clear link is still missing. The intent of this review is to summarize our current knowledge on the subject and attempt to propose a link. In the first part of this review we provide an overview of the physiological adaptation during the transition from pregnancy to lactation focusing on the alterations affecting the innate immune system and the inflammation occurring during this phase. In the second part of the review, we propose a relationship between the function of the innate immune system, the inflammatory conditions, and the metabolism in dairy cows during the transition from pregnancy to lactation with the intent to elucidate the driving cause of immune alterations occurring in this phase. In the third and final part, we review some novel dietary strategies to optimize the function of the innate immunity in dairy cows describing their mode of action and their applicability as an aid for dairy cows during the peripartal phase.