Transmissible spongiform encephalopathies (TSEs), also called prion diseases, are fatal, infectious, genetic or sporadic neurodegenerative disorders of humans and animals. In humans, TSEs are represented by Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, Fatal Familial Insomnia and Kuru. In animals, the most prominent prion diseases are scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) of cattle and chronic wasting disease (CWD) of deer and elk. A critical event in prion diseases is the accumulation in the central nervous system (CNS) of the abnormally folded PrP(Sc) protein that is the protease-resistant isoform of a normal cellular protein encoded by the host and called PrP(C). PrP(Sc) (also known as rPrP(Sc) or PrP27-30) represents the main marker of prion diseases and is routinely used in the reference method for the diagnosis of prion diseases. Most of the therapeutic strategies developed so far aimed at identifying compounds that diminish the levels of PrP(Sc), with variable success when tested in vivo. In this review, we present an alternative approach in which small molecules that induce PrP(Sc) oligomers are identified. By using virtual and cellular screenings, we found several thienyl pyrimidine compounds that trigger PrP(Sc) oligomerization and trap prion infectivity.