Prions are a self-propagating misfolded conformation of a cellular protein. Prions are found in several eukaryotic organisms with mammalian prion diseases encompassing a wide range of disorders. The first recognized prion disease, the transmissible spongiform encephalopathies (TSEs), affect several species including humans. Alzheimer's disease, synucleinopathies, and tauopathies share a similar mechanism of self-propagation of the prion form of the disease-specific protein reminiscent of the infection process of TSEs. Strain diversity in prion disease is characterized by differences in the phenotype of disease that is hypothesized to be encoded by strain-specific conformations of the prion form of the disease-specific protein. Prion therapeutics that target the prion form of the disease-specific protein can lead to the emergence of drug-resistant strains of prions, consistent with the hypothesis that prion strains exist as a dynamic mixture of a dominant strain in combination with minor substrains. To overcome this obstacle, therapies that reduce or eliminate the template of conversion are efficacious, may reverse neuropathology, and do not result in the emergence of drug resistance. Recent advancements in preclinical diagnosis of prion infection may allow for a combinational approach that treats the prion form and the precursor protein to effectively treat prion diseases.