Lesions that are hyperintense on T1 images after intravenous administration of gadolinium chelate represent focal areas of blood-brain barrier (BBB) disruption, which in multiple sclerosis (MS) are presumed to represent areas of active inflammation. T2 lesion burden early in the disease is the best known magnetic resonance imaging (MRI) predictor of long-term disability and brain atrophy. Several imaging approaches have been proposed to provide additional pathologic specificity with greater ability to monitor tissue integrity both within lesions visible on standard imaging, normal appearing brain tissue (NABT), and gray matter (GM). Phase 1 trials aim to expose a relatively small number of subjects to a new medication for a short period of time, monitoring primarily for safety concerns. MRI-based studies have become standard for Phase 2 (proof-of-concept) trials of disease modification in MS. Primary outcomes for Phase 3 (pivotal) trials remain relapses and disability progression.