The main goals of this article have been to summarize our current understanding of the biology of PrP, the propagation of prions, and the etiology and pathogenesis of each form of prion disease (familial, sporadic, and infectious); and to review current rational pharmacologic strategies for treatment of prion diseases. Each of these subjects is presented primarily from the perspective of investigations performed by the prion disease research laboratories at the University of California in San Francisco and by its many collaborators in the United States and abroad. This review focuses on key results from the hundreds of transgenic mouse lines expressing different PrP constructs that have been used to determine the roles played by different PrPSc and PrPC domains in prion propagation and the prion disease phenotype.