AIDS generated a significantly increased interest in the pathogenesis, clinical manifestations, and treatment of progressive multifocal leukoencephalopathy (PML), a disease previously considered to be very rare. Scrutiny increased after a second wave of PML following the introduction of biological agents, in particular, natalizumab and efalizumab. While efalizumab, a lymphocyte function-associated antigen 1 inhibitor marketed for use in psoriasis, has been removed from the market, natalizumab, an α4β1 and α4β7 integrin inhibitor, remains widely used in the treatment of multiple sclerosis (MS). Approximately 400 cases of natalizumab-associated PML have been reported from 2005 to August 2013. Additionally, other therapies currently employed or under development for the treatment of MS may also be associated with PML, such as mycophenolate mofetil, rituximab, and alemtuzumab. Therefore, practitioners using these medications need to understand the risks associated with these agents, ways to mitigate the risk, and treatment of PML and the related condition PML immune reconstitution inflammatory syndrome. PML associated with the use of therapeutic agents, especially, natalizumab, does share similarities with HIV-related PML; however, distinct differences exist. Radiographically isolated PML is seen more commonly with natalizumab-associated PML and the disease appears to be heralded more often by cognitive and behavior disturbances. Furthermore, the mortality of natalizumab-associated PML is substantially lower. Risk mitigation strategies have been developed for the natalizumab-associated PML, which has been convincingly demonstrated to be linked to duration of therapy, JC virus seropositivity, and the prior use of immunosuppressive agents.