Natalizumab (Tysabri), Biogen Idec/Elan) is a humanised neutralising antibody directed against alpha4 integrin expressed by leukocytes. Although it is an effective therapy for multiple sclerosis (MS), the serious adverse effect of progressive multifocal leukoencephalopathy (PML) resulted in its voluntary withdrawal from the market by Biogen Idec/Elan in February 2005. This has raised debates on whether PML was caused by blocking leukocyte trafficking-mediated immune suppression or by other effects through targeting alpha4 integrin per se. The authors propose that natalizumab-associated PML is a target-specific side effect predominantly due to the combination of: i) blocking leukocyte trafficking to peripheral organs resulting in reduced immune surveillance; ii) mobilisation of PML-causative JC virus-carrying bone marrow precursor cells and splenic marginal zone B cells; and iii) migration of these cells to sites of inflammation such as the brain. Therefore, combination of these effects is, so far, specific for the target alpha4 integrin and should not occur in general when interfering with other targets involved in leukocyte trafficking.