A misfolded isoform of the prion protein (PrP) is the essential component of the prion diseases' agent. The prion concept has progressively gained acceptance, in a large part thanks to the realization that it played a role not only in the transmissible spongiform encephalopathies, but also in the non-Mendelian propagation of self-perpetuating phenotypes of the yeast Saccharomyces cerevisiae. Uncertainties about the nature of the agent and the function of PrP have fostered searches of nucleic acid ligands of the protein. In vitro methods of nucleic acid evolutions have been used to identify RNAs or DNAs that bind PrP, towards the triple objective of i) setting up new diagnostic tools, ii) identifying nucleic acids with which PrP may interact, as part of its physiological or pathological function, and iii) elucidating the pathological transconformation of PrP. This review will focus on these studies, their methods, the knowledge acquired from them about the prion protein, and the possibilities that they offer in the areas of diagnosis and therapy of prion diseases.