Prion diseases are a new class of transmissible diseases whose transmission agent is composed of a misfolded protein. The existence of two forms (the native form and the misfolded form) from the same protein challenges the central dogma of the protein folding theory –‘one sequence, one structure’. Generally, scientists believe that there must be either a post translational modification or environmental factors involved in the structural transition. This review summarized the historical events which lead to the prion concept and our current understanding about prion disease.