Prions present a most fascinating biological conundrum. These proteinaceous particles seem to propagate through a chain reaction in which a host protein, PrPC, is post-translationally misfolded to form new prions. By this mechanism they 'replicate' without involvement of specific nucleic acids. Due to their unique modus operandi, prions cause disorders tat can be infectious, inherited and sporadic. Transgenetics has been invaluable in helping to understand this unique phenomenon. Here we describe some of the most salient contributions of transgenic mice to this field.