Background and purpose: Although the first-line disease-modifying therapies (DMTs) interferon beta and glatiramer acetate have a favourable benefit-to-risk profile, they are only partially effective for treating relapsing-remitting multiple sclerosis (RRMS). The optimization of treatment in patients who do not show a maximum response to first-line therapy is critical for achieving the best long-term outcomes. Treatment strategies for patients with a suboptimal response include switching to another first-line DMT or a second-line DMT. Natalizumab and fingolimod are approved for RRMS with high disease activity in the European Union and Canada. Methods: A comprehensive literature search for articles published between 1990 and April 2012 was undertaken.Results: This review discusses key clinical and safety data for fingolimod and natalizumab, particularly in the patient subgroups for whom these treatments are approved. Benefit-to-risk profiles, including first-dose cardiovascular effects associated with fingolimod and the risk of progressive multifocal encephalopathy with natalizumab, are discussed. Conclusion: A descriptive comparison of fingolimod and natalizumab is provided in the context of the decision-making process of how and when to switch patients who have a suboptimal response to first-line therapy.