Prion diseases are rare fatal neurodegenerative diseases of humans and other animals. The hallmark pathological features of TSEs are the spongiform degeneration of the brain, extensive neuronal loss, astrogliosis, and accumulation in the brain of a misfolded form of the prion protein (PrP). It has been proposed that PrP conformational changes may lead to the loss of physiological function of PrP or to acquisition of a neurotoxic activity by the misfolded protein, which may promote directly neuronal dysfunction. Alternatively, misfolded and aggregated prion protein may cause disease by inducing a chronic inflammatory reaction in the brain, leading to extensive brain damage mediated by reactive astrocytes and activated microglia. The aim of this article will be to review the different mechanisms that could relate PrP misfolding with brain degeneration and the emergence of TSE.