Natalizumab (TYSABRI(®)), a specific α4-integrin antagonist, is approved as a second-line treatment of relapsing-remitting MS (RRMS) patients who fail therapy with interferons or as first-line treatment of patients with highly active relapsing-remitting disease. Since the market introduction of natalizumab as a monotherapy in July of 2006, 111 cases of PML have been reported in natalizumab-treated MS patients as of April 2011. This review focuses on the available data regarding risk stratification for PML under long-term natalizumab therapy, and summarizes the current approach for PML management, as a natalizumab treatment complication is not necessarily associated with a fatal outcome. There is a need for development of surrogate markers that would help to better define the risk of PML in individual patients.