Recently, much has been learned about the molecular mechanisms involved in the pathogenesis of picornaviruses. This has been accelerated by the solving of the crystal structures of many members of this virus family. However, one stage of the virus life cycle remains poorly understood: uncoating. How do these simple but efficient pathogens protect their RNA genomes with a stable protein shell and yet manage to uncoat this genome at precisely the right time during infection? The purpose of this article is to review the current state of knowledge and the most recent theories that attempt to answer this question. The review is based extensively on structural data but also makes reference to the wealth of biochemical information on the topic.