Epilepsy is one of the most common neurological disorders. Temporal lobe epilepsy (TLE) represents the most frequent epilepsy syndrome in adult patients with resistance to pharmacological treatment. In TLE, the origin of seizure activity typically involves the hippocampal formation, which displays major neuropathological features, described with the term hippocampal sclerosis (HS). The expansion of neurosurgical epilepsy programs has offered the possibility of disposing of clinically well-characterized hippocampal tissue, so that the analysis of molecular mechanisms underlying the structural and functional reorganization occurring in the hippocampus and neighboring areas in TLE patients can be done on a large scale. The recent development of molecular biological technologies permits the analysis of changes in the expression of a large number of genes. This has opened new perspectives for epilepsy research. However, the hippocampal specimens obtained from patients with TLE most often represent an advanced stage of the pathology. For this reason, animal models that reproduce the clinical and histopathological features of TLE are helpful in detecting the early development of the pathological cascade leading to TLE with HS. An overview of recent data of gene expression profiles in human and experimental TLE is presented along with a discussion of the relevance of functional genomics, to develop new hypotheses and to detect likely candidate genes involved in epileptogenesis, as well as possible target molecules for new therapeutic approaches.