In epilepsy, seizures and comorbidities (e.g., cognitive deficits and depression) occur when specific thresholds are crossed. These thresholds depend on the diathesis (or vulnerability) of a given individual. The diathesis is controlled by multiple genetic and environmental factors. Diathesis changes over multiple timescales: on a daily basis, and as part of the development/aging processes, etc. The diathesis-epilepsy model introduced here provides a conceptual framework to understand how past events (e.g., a very stressful event) can directly influence the occurrence of epilepsy and comorbidities later in life. Experimental evidence supports this model, and the existence of biomarkers predictive of a vulnerability state have led to the development of preventive therapeutic strategies. Epigenetic modifications could be a key determinant of diathesis. Their role is discussed.