Dairy producers rely heavily on advisors with deep expertise in nutrition, reproduction, and health. However, a shift is occurring, driven by both farm size and advances in biology. Larger dairy businesses can investigate management options with a degree of precision never before possible; simultaneously, the lines between the metabolic, immune, and reproductive systems are becoming blurred. For example, new research has revealed a surprising role for immune cells in regulating metabolism and documented the nutrient requirements of the immune system. The gut epithelium has garnered new attention as a tissue that actively manages the commensal microbiome, entrains the responses of the neonatal immune system, and provides a barrier limiting movement of molecules from the gut lumen. New hormone discoveries have added adipose tissue, bone, and muscle to the list of endocrine organs. Finally, nutrients are now seen not only as substrates and cofactors, but also as signals that can alter cellular function. What does all of this mean for the dairy industry? Consultants increasingly need to reach across disciplinary boundaries to best support the physiology of the cow. However, research is needed to move beyond proof-of-principle findings toward applications in dairy cattle. Key unanswered questions include: the degree to which roles of the hindgut in monogastrics translate to ruminants; whether host/microbe crosstalk also occurs in the rumen; whether hormone release by storage organs during a catabolic state affects reproductive function; and the degree to which immunostimulation by dietary signals enhances or disrupts health and productivity. It is critical to address these questions with a 2-pronged approach. Mechanistic studies provide a nuanced understanding of signal interactions, but large-scale commercial studies are also needed to evaluate effects on multiple production outcomes in the environment of interest. Incorporating all aspects of animal health and productivity in management decisions will remain an art for the foreseeable future, but this should not dissuade the industry from pursuing a more holistic approach to management of the cow.