The fasciola cinereum (FC) neurons in the posterior hippocampal tail are identified as a key seizure node in both mice and humans with epilepsy. These neurons are highly active during seizures and can be targeted for intervention. In mice, optogenetic inhibition of FC neurons significantly reduced seizure duration. In humans, FC involvement was observed in six patients with epilepsy, and targeted lesioning of the FC in one patient reduced seizure burden after anterior mesial temporal structures were ablated. The FC is a critical node in the seizure propagation network in mesial temporal lobe epilepsy (TLE) and may also play a role in other forms of epilepsy, including temporal and non-temporal neocortical epilepsy. The FC is a viable therapeutic target in humans, as demonstrated by the successful reduction of seizures in a patient after FC ablation. The study highlights the FC as a promising interventional target for epilepsy treatment, potentially improving outcomes for patients who do not respond to conventional surgical resection. The findings suggest that targeting the FC could be an important addition to current surgical approaches for TLE.The fasciola cinereum (FC) neurons in the posterior hippocampal tail are identified as a key seizure node in both mice and humans with epilepsy. These neurons are highly active during seizures and can be targeted for intervention. In mice, optogenetic inhibition of FC neurons significantly reduced seizure duration. In humans, FC involvement was observed in six patients with epilepsy, and targeted lesioning of the FC in one patient reduced seizure burden after anterior mesial temporal structures were ablated. The FC is a critical node in the seizure propagation network in mesial temporal lobe epilepsy (TLE) and may also play a role in other forms of epilepsy, including temporal and non-temporal neocortical epilepsy. The FC is a viable therapeutic target in humans, as demonstrated by the successful reduction of seizures in a patient after FC ablation. The study highlights the FC as a promising interventional target for epilepsy treatment, potentially improving outcomes for patients who do not respond to conventional surgical resection. The findings suggest that targeting the FC could be an important addition to current surgical approaches for TLE.