Prion diseases are associated with the conversion of the cellular prion protein (PrP C), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrP Sc) that accumulates in brain tissues of affected individuals. PrP Sc is a self-catalytic protein assembly capable of recruiting native conformers of PrP C, and causing their rearrangement into new PrP Sc molecules. Several previous attempts to identify therapeutic agents against prion diseases have targeted PrP Sc, and a number of compounds have shown potent anti-prion effects in experimental models. Unfortunately, so far, none of these molecules has successfully been translated into effective therapies for prion diseases. Moreover, mounting evidence suggests that PrP Sc might be a difficult pharmacological target because of its poorly defined structure, heterogeneous composition, and ability to generate different structural conformers (known as prion strains) that can elude pharmacological intervention. In the last decade, a less intuitive strategy to overcome all these problems has emerged: targeting PrP C, the common substrate of any prion strain replication. This alternative approach possesses several technical and theoretical advantages, including the possibility of providing therapeutic effects also for other neurodegenerative disorders, based on recent observations indicating a role for PrP C in delivering neurotoxic signals of different misfolded proteins. Here, we provide an overview of compounds claimed to exert anti-prion effects by directly binding to PrP C, discussing pharmacological properties and therapeutic potentials of each chemical class.