Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system that is more common in women than in men, by a factor of approximately 3:1. Canada has the fifth-highest worldwide prevalence at 240 per 100,000 persons. MS is classified into four subtypes, with approximately 85% to 90% of MS patients having the relapsing-remitting type of MS (RRMS). In MS, the frequency of relapse is highly variable, but tends to be more frequent in the first few years of disease onset. The therapeutic aims of MS drugs are to lower the frequency of relapses, decrease the lasting effects of relapses, prevent or decrease disability that is the result of disease progression, and promote tissue repair. In Canada, the earliest available disease-modifying treatments for MS include interferons (interferon beta-1a and interferon beta-1b) and glatiramer acetate, approved by Health Canada in the 1990s. Natalizumab, administered via intravenous infusion, was approved by Health Canada in 2006 for the treatment of RRMS; however, there are some safety concerns regarding natalizumab because of its association with progressive multifocal leukoencephalopathy (PML), a rare demyelinating neurological disorder caused by the reactivation of the JohnCunningham virus (JC Virus). More recently, fingolimod — the first oral agent for the treatment of RRMS — was approved by Health Canada in 2011. Patients express a desire for oral agents over injectables; however, the price of fingolimod is considerably higher than that of either the interferons or glatiramer acetate and this drug has not been considered to be cost-effective in all patients studied. In addition, Health Canada monographs for both natalizumab and fingolimod indicate that these agents are generally recommended for patients with inadequate response or intolerance to other therapies for MS. Dimethyl fumarate, a new oral agent, was approved by Health Canada for the treatment of RRMS during the undertaking of this systematic review in 2013. In addition, a number of new disease-modifying therapies (both oral and injectable) for the treatment of MS are in development. These include alemtuzumab (injectable) and teriflunomide (oral), which are soon expected to enter the Canadian market. The effectiveness and safety of available MS treatments, relative to other active comparators, are not well-established. The emergence of novel oral and injectable agents necessitates consideration of their place in therapy, including the potential for combination therapy. Thus, the comparative clinical and cost-effectiveness of currently available and emerging disease-modifying agents for RRMS, both alone and in combination, need to be determined.