Over the past two decades, major advances have been made in the development of disease-modifying agents (DMAs) for multiple sclerosis (MS), and nine agents are now licensed for use in the treatment of MS in the United States. Clinical trials have demonstrated that a number of investigational agents have beneficial effects on clinical and radiographic measures of disease activity, thus the repertoire of available DMAs in MS will likely continue to expand moving forward. Although many of the first-line DMAs have the benefits of established long-term safety and tolerability, in some patients, treatment with one of the more potent novel agents may be appropriate. However, the use of novel agents must be approached with caution, since short-term clinical trials give little information on the long-term efficacy and safety of novel DMAs in MS patients. This chapter will consider the efficacy and safety of both established and investigational agents for the treatment of MS.