Leucine‐rich glioma‐inactivated (LGI) protein was first thought to have a suppressor effect in the formation of some cancers. Developments in physiology and medicine made it possible to characterize the function of the LGI protein family and its crucial role in different conditions more precisely. These proteins play an important role in synaptic transmission, and dysfunction may cause hyperexcitability. Genetic mutation of LGI1was confirmed to be the cause of autosomal dominant lateral temporal lobe epilepsy in humans. The LGI2 mutation was identified in benign familial juvenile epilepsy in Lagotto Romagnolo (LR) dogs. Cats with familial spontaneous temporal lobe epilepsy have been reported, and the etiology might be associated with LGI protein family dysfunction. In addition, an autoimmune reaction against LGI1 was detected in humans and cats with limbic encephalitis. These advances prompted a review of LGI protein function and its role in different seizure disorders.