Monoclonal antibodies were designed to extend therapeutic options in the treatment of chronic inflammatory and neoplastic diseases by the specific blockade of pathophysiologically relevant molecules. Natalizumab (Tysabri®, Biogen/Elan), a humanized, monoclonal antibody against alpha-4-integrin, is the first promising example for the treatment of relapsing-remitting multiple sclerosis. In initial phase II studies, treatment with natalizumab to a significant decline of Gadolinium-enhancing (Gd⁺) T1-lesions and reduction of the volume of Gd⁺ lesions on MRI-scans. In the AFFIRM phase-III-trial, the relapse and progression rate in natalizumab-treated patients suffering from relapsing-remitting MS (RRMS) was significantly reduced compared with placebo. Three patients treated with natalizumab developed progressive multifocal leukencephalopathy (PML), an infection of the CNS caused by the Polyomavirus JC. The drug was temporarily phased out of the market, but under strict obligations it was reauthorized for the single treatment regimen of active relapsing-remitting multiple sclerosis. For the assessment of benefits and risks and also adverse effects of new drugs developed for the treatment of chronic diseases like multiple sclerosis long-term-trials need to be conducted. Until these data are available the use of natalizumab should be restricted to centres with wide experience in the treatment of multiple sclerosis.