Prion diseases are a group of fatal neurodegenerative diseases caused by the misfolding of cellular prion protein (PrP(C)) into pathogenic conformers (PrP(Sc)). Although no effective therapies for prion diseases are currently available, a number of small molecule inhibitors have been identified that are capable of reducing or eliminating PrP(Sc) in prion infected cells. However, recent experiments have shown that upon sustained treatment, prions have the capacity to evolve into drug resistant conformations. These studies suggest that the mechanism of prion strain adaptation involves rare conformational conversions followed by competitive selection among the heterogeneous pool of PrP(Sc) conformers. The plasticity of prion conformers makes PrP(Sc) a particularly challenging drug target and suggests that combination drug therapies or targeting of PrP(C) may be required for effective therapy. In this review, we highlight recent literature that demonstrate the phenomenon of prion drug resistance and strain specificity, and discuss potential ramifications for therapeutic efforts against prion diseases.