Poliomyelitis has long served as a model for studies of viral pathogenesis, but there remain many important gaps in our understanding of this disease. It is the intent of this review to highlight these residual but important questions, in light of a possible future moratorium on research with polioviruses. Salient questions include: (1) What cells in the gastrointestinal tract are initially infected and act as the source of excreted virus? (2) What is the receptor used by mouse-adapted strains of poliovirus and how can some polioviruses use both mouse and primate receptors? (3) What determines species differences in susceptibility of the gastrointestinal tract to polioviruses? Why cannot PVR transgenic mice be infected by the natural enteric route? (4) Why are neuroadapted polioviruses unable to infect nonneural cells? (5) What is the role of postentry blocks in replication as determinants of neurovirulence? (6) What route(s) does poliovirus take to enter the central nervous system and how does it cross the blood-brain barrier? (7) Why does poliovirus preferentially attack lower motor neurons in contrast to many other neuronal types within the central nervous system? (8) Does cellular immunity play any role in recovery from acute infection or in vaccine-induced protection? (9) In which cells does poliovirus persist in patients with gamma-globulin deficiencies? (10) Is there any evidence that poliovirus genomes can persist in immunocompetent hosts? (11) Why has type 2 poliovirus been eradicated while types 1 and 3 have not? (12) Can transmission of vaccine-derived polioviruses be prevented with inactivated poliovirus vaccine? (13) What is the best strategy to control and eliminate vaccine-derived polioviruses?