Evidence of focal white matter inflammation on MRI can be related to relapses and chronic disability. The strength of the relationship depends on the stage of the disease. The predictive value is stronger early in the course of MS, when the focal white matter lesions are more important in the pathogenesis of MS. As the disease progresses, the predictive value of white matter lesions weakens and measures related to other, more diffuse aspects of the disease strengthen. Thus, lesion activity on MRI can be helpful as a guide to therapy, particularly early in the disease. Appropriate MRI criteria for a suboptimal response to therapy are not clear and may depend on the therapy being evaluated. The fact that diffuse pathology tends to progress despite effective suppression of focal inflammation is a cause for concern and needs to be addressed with new approaches to therapy that are more effective against this aspect of the disease.