Natalizumab is the first monoclonal antibody approved for the treatment of relapsing multiple sclerosis. Pivotal trials demonstrated the efficacy of natalizumab on clinical and paraclinical measures of disease activity and disability progression. Although a direct comparison has not been performed yet, natalizumab seems to be more efficacious than the currently available immunomodulant drugs, such as IFN-β and glatiramer acetate. Despite its efficacy, the occurrence of an increased risk of progressive multifocal leukoencephalopathy with the treatment, raises concerns about its widespread use in multiple sclerosis patients. This paper provides an overview of the most relevant results from the Phase I–IV studies on natalizumab and highlights the challenges addressed to minimize and manage its adverse events in clinical practice.