In prion diseases, neuropathology has remained the most important tool to give a definite diagnosis, and neuropathological research has contributed significantly to our current pathogenetic understanding. Immunohistochemistry for the disease-associated prion protein (PrP(Sc)) is indispensable for the neuropathological confirmation of prion diseases. The amount and distribution of PrP(Sc) deposits do not always correlate with type and severity of local tissue damage. PrP(Sc) deposition occurs only where neuronal parenchyma is present; in scarred infarctions with prominent gliosis, PrP(Sc) does not accumulate. Early, severe and selective loss affects a subset of inhibitory GABAergic neurons both in human and experimental prion diseases. The central pathogenetic cascade includes oxidative stress to neurons and their apoptosis. New patterns of PrP(Sc) immunoreactivity include granular ganglionic and tiny adaxonal PrP(Sc) deposits in peripheral nervous tissue, and dendritic cells and macrophages in vessel walls, suggesting that mobile haematogenous cells may be involved in spread of prions.