Natalizumab (Tysabri®) is a humanized monoclonal antibody against the α4 chain of integrins and was the first targeted therapy to be approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Natalizumab acts as a selective adhesion molecule antagonist, which binds very late antigen (VLA)-4 and inhibits the translocation of activated VLA-4-expressing leukocytes across the blood-brain barrier into the CNS. In a pivotal phase III clinical trial, natalizumab 300 mg intravenously every 4 weeks for 2 years in adults with RRMS significantly reduced the annualized relapse rate and the risk of sustained progression of disability compared with placebo, as well as significantly increasing the proportion of relapse-free patients at 1 and 2 years. Natalizumab also significantly reduced the number of T2-hyperintense, gadolinium-enhancing and T1-hypointense lesions on magnetic resonance imaging, and significantly reduced the volume of T2-hyperintense and T1-hypointense lesions compared with placebo. Natalizumab recipients generally experienced improved health-related quality of life at 1-2 years. Natalizumab was generally well tolerated in pivotal trials. The only adverse events that were more frequent with natalizumab monotherapy than with placebo were fatigue and allergic reactions. The main safety and tolerability issue with natalizumab is the incidence of progressive multifocal leukoencephalopathy (PML). As long as the risk of PML is managed effectively, natalizumab is a valuable therapeutic option for adults with highly active relapsing forms of multiple sclerosis.