New genetic investigation techniques, including next-generation sequencing, 
epigenetic profiling, cell lineage mapping, targeted genetic manipulation of 
specific neuronal cell types, stem cell reprogramming, and optogenetic 
manipulations within epileptic networks are progressively unraveling the 
mysteries of epileptogenesis and ictogenesis. These techniques have opened new 
avenues to discover the molecular basis of epileptogenesis and to study the 
physiologic effects of mutations in epilepsy-associated genes on a multilayer 
level, from cells to circuits. This manuscript reviews recently published 
applications of these new genetic technologies in the study of epilepsy, as well 
as work presented by the authors at the genetic session of the XII Workshop on 
the Neurobiology of Epilepsy (WONOEP 2013) in Quebec, Canada. Next-generation 
sequencing is providing investigators with an unbiased means to assess the 
molecular causes of sporadic forms of epilepsy and has revealed the complexity 
and genetic heterogeneity of sporadic epilepsy disorders. To assess the 
functional impact of mutations in these newly identified genes on specific 
neuronal cell types during brain development, new modeling strategies in 
animals, including conditional genetics in mice and in utero knock-down 
approaches, are enabling functional validation with exquisite cell-type and 
temporal specificity. In addition, optogenetics, using cell-type-specific Cre 
recombinase driver lines, is enabling investigators to dissect networks involved 
in epilepsy. In addition, genetically encoded cell-type labeling is providing 
new means to assess the role of the nonneuronal components of epileptic networks 
such as glial cells. Furthermore, beyond its role in revealing coding variants 
involved in epileptogenesis, next-generation sequencing can be used to assess 
the epigenetic modifications that lead to sustained network hyperexcitability in 
epilepsy, including methylation changes in gene promoters and noncoding 
ribonucleic acid (RNA) involved in modifying gene expression following seizures. 
In addition, genetically based bioluminescent reporters are providing new 
opportunities to assess neuronal activity and neurotransmitter levels both in 
vitro and in vivo in the context of epilepsy. Finally, genetically rederived 
neurons generated from patient induced pluripotent stem cells and genetically 
modified zebrafish have become high-throughput means to investigate disease 
mechanisms and potential new therapies. Genetics has changed the field of 
epilepsy research considerably, and is paving the way for better diagnosis and 
therapies for patients with epilepsy.