This chapter describes the natural history of multiple sclerosis and, in particular, reviews the controversy regarding the entity of benign multiple sclerosis. Based on the Olmsted County population prevalence cohort study performed at the Mayo Clinic, MS patients with EDSS scores of 2 or lower followed for a period of 5-10 years have a very small risk of developing disability over the next 10-20 years. Based on these findings, this chapter reviews the indications, efficacy, mode of action, and side effect profiles of the currently approved and available diseasemodifying agents for the treatment of multiple sclerosis. The efficacy of these agents is discussed based on the concepts of evidence-based medicine and the natural history of the disease. We review the arguments for and against treating all patients with MS. The authors propose an individualized approach to the use of these agents in the MS population.