According to the definition of epileptogenesis, "disease modification" refers to every clinically relevant therapeutic outcome which does not necessarily prevent epilepsy onset but significantly improves the disease course by reducing seizure burden and/or decreases concomitant comorbidities. In this light, understanding comorbidities development, their characteristics, and the neurobiological causes represents a major issue both in clinical and preclinical research. This chapter is summarizing and critically evaluating the preclinical improvements over time in the study of epilepsy comorbidities reconsidering some of them according to the newer results. Furthermore, we highlight limitations and possibilities both in the methods used and in the mechanisms considered. The latter have been analysed also as potential therapeutic targets for therapy development. Finally, differences and similarities between induced epilepsy models and genetic models have been underlined in the chapter.