Prion diseases are some of the most intriguing infectious disorders affecting the brains of humans and animals. The prevalent hypothesis proposes that the infectious agent is a misfolded protein that propagates in the absence of nucleic acid by transmission of its altered folding to the normal host version of the protein. This article details the evidence for and against the prion hypothesis, including results of recent studies in yeast, in which a prion phenomenon has also been identified. The evidence in favor of the prion model is very strong, but final proof-consisting of the generation of infectious prions in vitro-is still missing.