Prion diseases are characterised by neuronal loss, vacuolation (spongiosis), reactive astrocytosis, microgliosis and in most cases by the accumulation in the central nervous system of the abnormal prion protein, named PrPSc. In this review on the "cellular pathogenesis in prion diseases", we have chosen to highlight the main mechanisms underlying the impact of PrPC/PrPSc on neurons: the neuronal dysfunction, the neuronal cell death and its relation with PrPSc accumulation, as well as the role of PrPSc in the microglial and astrocytic reaction.