It is valuable to summarize the milestone study of prion diseases done in Japan for review in the journal Neuropathology in 2000. Many studies done in Japan promote world prion research activity, and also influence further research projects in other groups abroad. In this review the author focuses on the transmission experiment, the discovery of abnormal prion protein localization in the synaptic structures or follicular dendritic cells, and the genetic analysis of prion protein gene for the establishment of familial prion diseases.