In the majority of cases, epilepsy develops in three phases: (i) initial brain damaging insult (eg, head trauma, stroke, status epilepticus), resulting in (ii) epileptogenesis, which in turn leads to (iii) recurrent seizures (epilepsy). The current treatment of epilepsy, however, focuses exclusively on the prevention or suppression of seizures, ie, the end result of the disease process. Recent findings regarding the sequence of neurobiological changes leading to epilepsy and its molecular basis have raised the question of whether the disease process of epileptogenesis can be prevented, or at least modified in such a way that the epilepsy that develops is milder, easier to treat, non-progressive and without cognitive decline and drug-resistance. Furthermore, if epilepsy has already emerged, can the harmful effects of seizures on the brain be alleviated? Experimental data indicate that attenuation of the severity of the initial insults associated with seizure activity by anti-epileptic drugs improves the outcome by reducing epileptogenesis, resulting in a milder disease. Although there are no true anti-epileptogenic compounds that interfere with the molecular cascades underlying epileptogenesis, there are several new concepts that offer new targets for the treatment of epileptogenesis and disease modification, including neurotrophins, neuropeptides, caspase inhibitors and anti-inflammatory agents.