Physical exercise is an effective preventive and therapeutic strategy to chronic diseases such as type-II diabetes and obesity, hence the term “EXERCISE IS MEDICINE”. A considerable portion of these health-promoting effects relate to the acute and chronic vascular adaptations to exercise. We now propose a putative CARNOSINE-HISTIDINE-HISTAMINE PATHWAY as a molecular mediator of these health-protective effects. CARNOSINE is an abundant dipeptide in skeletal muscle that can be readily degraded into its constituent amino acids β-alanine and HISTIDINE, of which the latter can be further processed to HISTAMINE. We hypothesise that physical exercise is the switch for activation of the pathway, resulting in a cascade of physiological events inside the skeletal muscle that regulate the exercise-induced vascular adaptations. Uncovering this NOVEL PHYSIOLOGICAL MECHANISM can provide a better understanding on how exercise induces functional vascular adaptations in health and disease. This knowledge will lead to the development of optimised physical exercise and supplementation prescriptions for both the healthy and patient population, which can ultimately lead to reducing the chronic disease burden.