As the global eradication of wild poliovirus nears, the World Health Organization (WHO) is addressing challenges unprecedented in public health. The live, attenuated oral poliovirus vaccine (OPV), used for more than four decades to interrupt poliovirus transmission, and the vaccine of choice for developing countries, is genetically unstable. Reversion of the small number of substitutions conferring the attenuated phenotype frequently occurs during OPV replication in humans and is the underlying cause of the rare cases of vaccine-associated paralytic poliomyelitis (VAPP) in OPV recipients and their close contacts. Whereas VAPP has long been recognized, two other adverse events have been identified more recently: (a) long-term excretion of highly evolved vaccine-derived polioviruses (VDPVs) in persons with primary immunodeficiencies, and (b) polio outbreaks associated with circulating VDPVs in areas with low rates of OPV coverage. Developing a posteradication strategy to minimize the risks of VDPV emergence and spread has become an urgent WHO priority.