Epilepsy affects approximately 3% of the population, and is usually defined as a tendency to experience recurrent seizures arising from periodic neuronal hyperexcitability of unknown causes. Different genetic factors, through various mechanisms, can cause this abnormal neuronal behavior. The etiology of epilepsy is a major determinant of clinical course and prognosis. Many of the genes that have been implicated in idiopathic epilepsies code for ion channels, whereas a wide spectrum of syndromes where epilepsy is a main clinical feature are caused by mutated genes that are involved in functions as diverse as cortical development, brain malformations, mitochondrial function, and cell metabolism. Similarly, different conditions as hypoxia, trauma, infections, or metabolic unbalances can develop epileptic syndromes where upregulation of several genes could be related to the epileptogenic mechanisms. The most common human genetic epilepsies display a complex pattern of inheritance, and the susceptible genes are largely unknown. However, major advances have recently been made in our understanding of the genetic basis of monogenic inherited epilepsies. As we continue to unravel the molecular genetic basis for epilepsies, it will increasingly influence their classification and diagnosis. A majority of epileptic patients may control their crisis with anticonvulsant drugs, however 30%-40% became refractory to pharmacological therapies and require surgical treatment. The challenge of the molecular revolution will be the design of the best treatment protocols based on genetic profiles that include both the specific mechanistic etiology of the epilepsies, as well as their potential refractory behavior to current medications. This includes also the design of new therapeutic agents and targets, so as to reduce the number of cases with refractory epilepsy and epileptogenesis, and perhaps avoid the current surgical treatment (a procedure that was first described more than 4000 years ago) except as a last option.