There is increasing impetus to begin disease-modifying therapy for relapsing multiple (R-MS) early, before the development of irreversible tissue damage and resultant permanent disability. However, all of the currently-approved therapies for relapsing multiple sclerosis are only partially effective for patients as a group. Treatment failure can be due to noncompliance with therapy, intolerable adverse effects, the development of neutralizing antibodies, or non-responsive disease. Neurologists managing patients on disease-modifying therapy for R-MS must remain vigilant for these issues and take appropriate action when necessary.