In 1988, the World Health Assembly resolved to eradicate polio worldwide. The Global Polio Eradication Initiative (PEI) of the World Health Organization (WHO) has led to a decline in global polio incidence, from an estimated 350,000 cases in 1988 to fewer than 2,000 reported cases in 2005, and polio remains endemic to only four countries (Afghanistan, India, Nigeria, and Pakistan). However, two additional obstacles to global eradication involve vaccine-derived polioviruses (VDPVs). Polio outbreaks continue to be associated with circulating vaccine-derived polioviruses (cVDPVs) in areas with low oral poliovirus vaccine (OPV) coverage. In addition, long-term excretion of neurovirulent immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) can lead to poliovirus spread to contacts. Overcoming these obstacles is challenging. High rates of OPV coverage will prevent all poliovirus spread, including spread of VDPVs, but will not prevent establishment of prolonged VDPV infections in certain persons with B-cell immunodeficiencies (i.e., having defects in antibody production). Inevitable gaps in vaccination coverage will give rise to cVDPVs as long as OPV use continues. This report updates a previous report on VDPVs and describes the potential implications of VDPVs in the final stages of global polio eradication. The findings underscore the critical need to strengthen strategies to prevent emergence of VDPVs and to stop all OPV use once wild polioviruses (WPVs) are eradicated.