Epilepsy often follows a focal insult, and develops with a time delay so to reveal a complex cascade of events. Both clinical and experimental findings suggest that the initial insult triggers a self-promoted pathological process, currently named epileptogenesis. An early phase reflects the complex response of the nervous system to the insult, which includes pro-injury and pro-repair mechanisms. Successively, the sprouting and probably neurogenesis and gliosis set up the stage for the onset of spontaneous seizures. Thus, local changes in excitability would cause a functional change within a network, and the altered circuitry would favor the seizures. A latent or clinically silent period, as long as years, may precede epilepsy. In spite of the substantial knowledge on the biochemical and morphological changes associated with epileptogenesis, the mechanisms supposedly underlying the process are still uncertain. The uncertainty refers mostly to the silent period, a stage in which most, if not all, the receptor and ion changes are supposedly settled. It is tempting to explore the nature of the factors promoting the epileptogenesis within the notional field of neurodegeneration. Specifically, several observations converge to support the hypothesis that a prion-like mechanism promotes the "maturation" process underlying epileptogenesis. The mechanism, consistently with data from different neurodegenerative diseases, is predictably associated with deposition of self-aggregating misfolded proteins and changes of the ubiquitin proteasome and autophagy-lysosome pathways.