Abstract BACKGROUND Cortico-amygdalohippocampectomy (CAH) is effective for mesial temporal lobe epilepsy (mTLE). Concerns regarding surgical morbidity have generated enthusiasm for more minimally invasive interventions. A careful analysis of current data is warranted before widespread adoption of these techniques. OBJECTIVE To systematically review the use of laser interstitial thermal therapy (LITT), stereotactic radiosurgery (SRS), radiofrequency thermocoagulation (RF-TC), and focused ultrasound for mTLE. METHODS Major online databases were searched for prospective observational studies, randomized clinical trials, and retrospective studies (>50 patients), including mTLE patients. Outcomes of interest were seizure freedom (Engel I), complications and re-operation rates, and neuropsychological and quality-of-life (QoL) data. RESULTS Nineteen publications were identified. At ≥6 mo postoperatively, LITT (9/19) Engel I outcomes ranged from 52% to 80%. SRS (3/19) has a latency period (52%-67%, 24-36 mo postoperatively) and the radiosurgery vs. open surgery for epilepsy (ROSE) trial reported inferiority of SRS compared to CAH. RF-TC (7/19) demonstrated variable seizure freedom rates (0%-79%) and high re-operation rates (0%-90%). Twelve studies reported neuropsychological outcomes but QoL (4/19) was not widely reported, and few studies (3/19) assessed both. Study quality ranged from fair to good. CONCLUSION Based on nonrandomized data, LITT has compelling evidence of efficacy; however, comparisons to surgical resection are lacking. SRS has a latency period and is inferior to CAH (ROSE trial). RF-TC is a less resource-intensive alternative to LITT; however, comparisons of efficacy are limited. Additional studies are needed before minimally invasive procedures can supplant standard surgery.