The physiology of red blood cells (RBCs) in any animal is always different to that of most other cell types. It also varies to a surprising extent across different species. Horses, like most animals, are very well adapted to their lifestyle. For horses, this includes an impressive capacity for exercise—the maximal O2 consumption of horses is about double that of elite human athletes. Intense exercise imposes major stresses on their body, particularly on the cardiovascular, respiratory, and thermoregulatory systems, necessitating many unique adaptations. How does the physiology of horse RBCs support this unique biology? We focus here on the importance of RBC rheology, lactate and amino acid permeability, and ion and water homeostasis. While these areas will be directly relevant to RBC function, they may also contribute significantly to the overall physiology of the horse, through their interactions with other body systems. Areas of interest include the contribution of RBCs to vascular resistance and perfusion pressures, O2 delivery, interorgan delivery of substrates for energy and for protein synthesis, and electrolyte and fluid homeostasis. The special features of horse RBC physiology are highlighted, how they differ in respect to human RBCs, and how they contribute holistically. Areas requiring further elucidation are indicated.