Increased animal productivity and production variability are due to changes in nutrient partitioning. The coordination of nutrient trafficking is an incredibly complex system and how tissues/systems are reprioritized or de-emphasized during different physiological states is controlled by homeostatic and homeorhetic adaptations that probably incorporate every tissue and physiological system. There are a variety of situations in an animal’s life-cycle that challenges homeostasis. The metabolic adaptations that cows utilize to copiously synthesize milk following parturition are unfortunately often referred to as “metabolic stress.” Metabolic maladaptation to lactation results in ketosis and this is in part either caused by inadequate feed intake or causes reduced feed intake. Regardless, although heavily researched for the last 3 decades the specific etiology of periparturient ketosis remains elusive as it unclear why a small percentage of cows are susceptible (or predisposed?) to metabolic imbalances following calving. Heat stress (HS) compromises efficient animal production and jeopardizes animal welfare and HS animals also have a unique metabolic and physiological fingerprint that is uniquely different than their nutritional status predicts. The origin of both ketosis and HS issues may lie at the gastrointestinal tract. Increased intestinal permeability to lipopolysaccharide (LPS) and other luminal contents results in local and systemic inflammatory responses. LPS interferes with hepatic lipid trafficking, stimulates insulin secretion and influences systemic fuel selection. We demonstrated that both ketotic and HS animals have markedly increased circulating markers of leaky gut. We have also shown that reduced feed intake (a conserved response to stress) compromises intestinal integrity in both thermal-neutral monogastrics and ruminants. Thus, stressors that physically prevent ad libitum feed intake or cause voluntarily reductions in feed take may share a common mechanism(s). Defining the physiology and mechanisms that underlie how intestinal barrier dysfunction jeopardizes animal performance is critical for developing approaches to ameliorate current production issues.