MRI is a powerful tool for evaluating structural and functional alterations in the optic nerve in experimental animal models of human disease. MRI-histopathological correlations have provided important insights into the pathogenesis of disease. Paramagnetic contrast agents have been used to serially visualize the foci and severity of disruption of the blood-optic nerve barrier and physiological neuronal alterations in living animals. Here I review the experience of our group in optic nerve imaging of experimental autoimmune encephalomyelitis and neurodegeneration induced by genetic manipulation of respiratory chain enzymes.