Changes in protein conformation drive most biological processes, but none have seized the imagination of scientists and the public alike as have the self-replicating conformations of prions. Prions transmit lethal neurodegenerative diseases by means of the food chain. However, self-replicating protein conformations can also constitute molecular memories that transmit genetic information. Here, we showcase definitive evidence for the prion hypothesis and discuss examples in which prion-encoded heritable information has been harnessed during evolution to confer selective advantages. We then describe situations in which prion-enciphered events might have essential roles in long-term memory formation, transcriptional memory and genome-wide expression patterns.