Tubulovesicular structures (particles ? TVS) are the only ultrastructural marker for all prion diseases as seen by thin-section electron microscopy as opposed to ?negative-staining' techniques. TVS are spheres or short rods of approximately 27 nm in diameter. That size of TVS is also the size of filter cut-off of infectivity as judged from the ultrafiltration studies and the size of the smallest infectious unit as recently estimated. TVS have been found in all naturally occurring and experimentally induced prion diseases, including variant Creutzfeldt-Jakob disease and human familial TSEs ? fatal familial insomnia and Gerstmann-Str?ussler-Scheinker disease. In longitudinal studies, the number of neuronal processes containing TVS correlates roughly with the incubation period and with infectivity. Hence, they are readily found in hamsters infected with the 263K strain of scrapie but it is very difficult to find them in human TSEs where titer is lower. The composition of TVS is unknown but they are not composed of PrP. Their consistent presence in all TSEs suggests the unexplained role at least of TSE pathogenesis.