Transmissible spongiform encephalopathies (TSEs) or prion diseases can be efficiently transmitted by blood. Significant progress has been made, in recent years, in the field of the TSEs’ pathognomonic marker (PrP^TSE) detection in blood; however, a routine blood test for the diagnosis of prion diseases is yet unavailable. This delay in developing a PrP^Sc-based blood test that can be introduced into routine clinical practice indicates that the challenges and limitations that may affect the reliability and feasibility of detecting PrP^Sc using blood still remain. This perspective summarizes the potential challenges and highlights those that still need to be overcome to enable the development of a routine blood test not only for prion diseases but also for prion-like neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, which involve related mechanisms. Furthermore, this mini-review highlights that in order to be able to develop a successful routine blood test for prion diseases, it may be essential to overcome all of the potential limitations not only because they hinder the identification of PrP^Sc in different ways, but also because these limitations are present heterogeneously in infected subjects.