Drug resistance is a refractory barrier in the battle against many fatal diseases caused by rapidly evolving agents, including HIV, apicomplexans and specific cancers. Emerging evidence suggests that drug resistance might extend to lethal prion disorders and related neurodegenerative amyloidoses. Prions are self-replicating protein conformers, usually ‘cross-β’ amyloid polymers, which are naturally transmitted between individuals and promote phenotypic change. Prion conformers are catalytic templates that specifically convert other copies of the same protein to the prion form. Once in motion, this chain reaction of conformational replication can deplete all non-prion copies of a protein. Typically, prions exist as ensembles of multiple structurally distinct, self-replicating forms or ‘strains’. Each strain confers a distinct phenotype and replicates at different rates depending on the environment. As replicators, prions are units of selection. Thus, natural selection inescapably enriches or depletes various prion strains from populations depending on their conformational fitness (ability to self-replicate) in the prevailing environment. The most successful prions confer advantages to their host as with numerous yeast prions. Here, I review recent evidence that drug-like small molecules can antagonize some prion strains but simultaneously select for drug-resistant prions composed of mammalian PrP or the yeast prion protein, Sup35. For Sup35, the drug-resistant strain configures original intermolecular amyloid contacts that are not ordinarily detected. Importantly, a synergistic small-molecule cocktail counters prion diversity by eliminating multiple Sup35 prion strains. Collectively, these advances illuminate the plasticity of prionogenesis and suggest that synergistic combinatorial therapies might circumvent this pathological vicissitude.