Nearly 100 years after its discovery poliovirus remains one of most thoroughly studied and best understood virus models for the molecular virologist. While poliovirus has been of vital importance for our insight into picornavirus biology at the cellular and biochemical level, it is ironic to note that, due to the early success in defeating poliomyelitis in the developed world through vaccination, many of the basic aspects of poliovirus pathogenesis remain poorly understood. This is chiefly due to the lack of an adequate and affordable animal model, save of old world monkeys. Fundamental questions, such as the identity of the target cells during the enteric phase of infection, or mechanisms of systemic spread are still unanswered. This review will attempt to summarize our current knowledge of the molecular biology of poliovirus, its pathogenesis, as well as recent advances in the areas of cell and tissue tropism and mechanisms of central nervous system invasion.