Objective: To review the pharmacological basis of use and clinical evidence for the benefit and safety of natalizumab (NAT) for the treatment of multiple sclerosis (MS) and Crohn's disease (CD). Methods: A literature search using PubMed and Ovid Medline was conducted and relevant articles published in the English language from the year 2000 to September 2009, containing the keyword, NAT, were reviewed. Additionally, professional meeting presentation abstracts, editorials, article bibliographies and information from the manufacturer were used. Results: NAT, a monoclonal antibody and first medication in the class of selective adhesions inhibitors tested in clinical trials, targets the trafficking and adhesion of leukocytes, inhibiting migration to sites of inflammation. It has been used successfully as monotherapy and in combination with interferon beta-1a or glatiramer acetate to decrease relapse rates and detectable lesions, and increase functional ability in patients with relapsing forms of MS. NAT has also shown benefit in CD unresponsive to standard immunosuppressive therapy. Major concerns with NAT use center on an association with progressive multifocal leukoencephalopathy (PML), but include the issue of antibody production to NAT and potential rebound effects following discontinuation of the drug. Conclusion: Clinical data suggest NAT provides benefit beyond standard therapies for MS and CD. However, concern about the serious adverse effect of PML will limit its use to patients in whom potential benefits outweigh possible risks.