Therapeutics are often administered to donkeys based on dosage and intervals recommended for horses because very few drugs have donkey-specific label indications. Yet differences between donkeys and horses in drug distribution, metabolism and elimination have been noted for most therapeutic agents studied. These differences can be partially explained by the donkey's unique physiology. Since their ancestors evolved in a desert environment, the modern donkey exhibits qualities that allow them to tolerate dehydration better than the horse and recover more quickly from its effects. Fluid balance and body water compartment partitioning differ from the horse and may have implications regarding drug distribution. Since donkeys are preferential browsers, differences in diet may have influenced evolutionary differences in metabolic disposition of drugs. It is important to acknowledge these differences when designing dose regimes for donkeys based on horse protocols in order to avoid either lack of efficacy or toxicity.