Immunometabolism represents the interface between immunology and metabolism, and is an emerging field of investigation in livestock biosciences. In human medicine, immunometabolism recognizes the link between obesity and the immune system, explicitly acknowledging that obesity-induced inflammation promotes onset of chronic disorders. More importantly, at the core of this concept is the recognition of “multilevel interactions between metabolic and immune systems,” implying “cross-talk” or “communication” among key cells and organs, which are orchestrated by unique mechanisms and their effectors. Such mechanisms correlate closely with health or disease status. The field of immunometabolism as it pertains to periparturient dairy cows is in its infancy. Classic studies before the 21st century defined the key metabolic, endocrine, and immune adaptations characterizing the transition into lactation. The advent of high-throughput technologies in the past decade further allowed the exploration of interrelationships among these systems. As a result of discoveries from that research, ongoing focus is on the bi-directional communication between immune and metabolic cells with signaling molecules derived intrinsically or as a result of intermediary metabolism or immune responses in tissues such as liver, adipose, and skeletal muscle. Both, macronutrients and micronutrients can be important effectors in the regulation of the immunometabolic response of the cow with effects often broad in nature. These responses are of great importance during the adaptation phase to lactation, as they seem to be key determinants of feed intake and milk production, reproduction, and health status. Management of total dietary energy supply and certain essential nutrients are examples of promising tools that can help regulate and enhance immunometabolic adaptations during the periparturient period and early lactation. A better understanding of the multilevel interactions among the various components of the metabolic and immune systems during the periparturient period has already led to identification of pathogenic mechanisms that underlie certain complications afflicting cows. Future research in this area should lead to promising therapeutic approaches.