Natalizumab is a monoclonal antibody, representing a new class of medication for treating relapsing multiple sclerosis (MS). Conventional treatments include interferons, glatiramer acetate and chemotherapies such as mitoxantrone and cyclophosphamide. These therapies offer only modest clinical benefits and are commonly not tolerated due to side effects. Natalizumab has been proven in large-scale, blinded, randomized, controlled trials to have an exceptional effect on preventing relapses, decreasing the risk of sustained progression of disability, and increasing the rate of disease-free patients over a 24-month period compared to placebo. These trials led to the speedy approval of natalizumab for treating relapsing MS, but its use was halted a few months after its induction after several cases of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease affecting the central nervous system. After a long deliberation by an FDA advisory panel and strong support from the MS community, natalizumab was reapproved with stringent restrictions including patient, provider and site registration. Natalizumab is now considered second-line therapy for patients who have failed first-line agents such as interferon or glatiramer acetate. As little is known about additional risk factors for PML and other potential infections, patients and providers must work together to carefully decide if potential benefits outweigh these rare but potentially devastating complications.