Transmissible spongiform encephalopathies (TSEs) are prion protein misfolding diseases that involve the accumulation of an abnormal β-sheet-rich prion protein aggregated form (PrP(sc)) of the normal α- helix-rich prion protein (PrP(c)) within the central nervous system (CNS) and other organs. On account of its large size and insolubility properties, characterization of PrP(c) is quite difficult. A soluble intermediate, called PrP(β) or β(o), exhibiting many of the same features as PrP(sc), can be generated using a combination of low pH and/or mild denaturing conditions. Here, we review the current knowledge on the following five issues relevant to the conversion mechanisms of PrP(c) to PrP(sc) : (1) How is the Stability of the Helical Structures in the Native PrP(c) Related to the Primary Structure of the PrP(c) (2) Why the Low pH Solution System is a Ideal Trigger of PrP(c) to PrP(sc) Conversion (3) How are the Structural and Dynamical Characteristics of the α-helixrich Intermediates Determined using NMR Data (4) How are the Premolten (PrP(α4) and PrP(αβ)) and β-Oligomer (PrP(β)) Intermediates Detected and Assayed, and (5) Can the Disordered N-terminal Domain be folded into the Structural Segment? Particularly, Chou's wenxiang diagram (http://en.wikipedia.org/wiki/Wenxiang_diagram) was introduced for providing an intuitive picture. This review may help to further understand the prion protein misfolding mechanism.