Prion diseases are fatal neurodegenerative disorders for which no effective therapies exist. Despite decades of drug discovery efforts, progress in developing disease-modifying treatments has been slow. However, recent advances have introduced novel therapeutic modalities targeting key aspects of prion pathology, including prion protein biogenesis, aggregation, and degradation. Advancements in diagnostic tools and highly sensitive prion detection methods are also playing a crucial role in enabling early and accurate diagnosis, which is essential for the timely application of emerging therapeutics. This chapter explores novel therapeutic modalities for prion diseases, focusing on small-molecule theranostics and compounds promoting prion protein degradation, RNA-based therapeutics, and gene therapy approaches. We critically assess the advantages and limitations of these therapeutic strategies, considering their development, efficacy, and translational potential. By leveraging these innovative modalities, the therapeutic toolbox for prion diseases is expanding, offering hope for the development of effective treatments.