Magnetic resonance imaging (MRI) has been extensively applied in the study of multiple sclerosis (MS), substantially contributing to diagnosis, differential diagnosis, and disease monitoring. MRI studies have significantly contributed to the understanding of MS through the characterization of typical radiological features and their clinical or prognostic implications using conventional MRI pulse sequences and further with the application of advanced imaging techniques sensitive to microstructural damage. Interpretation of results has often been validated by MRI-pathology studies. However, the application of MRI techniques in the study of neuromyelitis optica spectrum disorders (NMOSD) remains an emerging field, and MRI studies have focused on radiological correlates of NMOSD and its pathophysiology to aid in diagnosis, improve monitoring, and identify relevant prognostic factors. In this review, we discuss the main contributions of MRI to the understanding of MS and NMOSD, focusing on the most novel discoveries to clarify differences in the pathophysiology of focal inflammation initiation and perpetuation, involvement of normal-appearing tissue, potential entry routes of pathogenic elements into the CNS, and existence of primary or secondary mechanisms of neurodegeneration.