Prion diseases are among the most intriguing illnesses. Despite their rare incidence, they have captured enormous attention from the scientific community and general public. One of the most hotly debated issues in these diseases is the nature of the infectious material. In recent years increasing evidence has emerged supporting the protein-only hypothesis of prion transmission. In this model PrPSc (the pathological isoform of the prion protein, PrPC) represents the sole component of the infectious particle. However, uncertainties about possible additional factors involved in the conversion of PrPC into PrPSc remain despite extensive attempts to isolate and characterize these elusive components. In this article, we review recent developments concerning the protein-only hypothesis as well as the possible involvement of cellular factors in PrPC to PrPSc conformational change and their influence on the pathogenesis of prion diseases.