Acute flaccid paralysis (AFP) of the extremities and/or the muscles innervated by the cranial nerves encompasses a range of infectious, autoimmune, and acquired etiologies. Acute paralytic polio as a complication of poliovirus infection was once a common cause of acute weakness leading to paralysis among children. Due to successful global polio vaccination programs, polioviruses have been eliminated from the Western hemisphere. Globally, only two countries remain polio endemic, and a surge of optimism for complete global eradication came with the 2015 announcement that one of the three poliovirus types, type 2, has been successfully eradicated from the earth. Currently, from a clinical perspective, illnesses which most resemble acute poliomyelitis include neurologic complications that occur during infections with other viruses including non-polio enteroviruses, West Nile virus, and Zika virus. Guillain-Barré syndrome (GBS), a noninfectious autoimmune demyelinating illness, shares several characteristics with “polio-like” illnesses and is known to be triggered by several different infections. Fortunately, AFP is rare, but when it occurs, it is frightening. Given the potential life-threatening nature of the illness, it should always be handled as a medical emergency. Early recognition, hospitalization, and a measured diagnostic evaluation are key to guide proper management. Prognosis depends on the underlying cause and ranges from full recovery to permanent paralysis or death.