Abstract
Replacement, reduction and refinement (the 3R's) are the leading principles in translational research with animals. To be useful a model should also be clinically Relevant (the 4th R). Work in a non-human primate model of multiple sclerosis, the experimental autoimmune encephalomyelitis model, reveals an inherent conflict among these 4R principles. The impossibility to harmonize all 4R's forms a major challenge when the model is applied in preclinical drug development.