As the world is approaching the eradication of wild poliovirus serotype 1, the last of the three wild types, the question of how to maintain a polio-free world becomes imminent. To mitigate the risk of sporadic vaccine-associated paralytic polio (VAPP) caused by oral polio vaccines (OPVs) that are routinely used in global immunization programs, the Polio Antivirals Initiative (PAI) was established in 2006. The primary goal of the PAI is to facilitate the discovery and development of antiviral drugs to stop the excretion of immunodeficiency-associated vaccine-derived poliovirus (iVDPV) in B cell-deficient individuals. This review summarizes the major progress that has been made in the development of safe and effective poliovirus antivirals and highlights the candidates that have shown promising results in vitro, in vivo, and in clinical trials.