Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Approximately 9180 primary GBM tumors are diagnosed in the United States each year, in which median survival is up to 16 months. GBM eludes and resists typical cancer treatments due to the presence of infiltrative cells beyond the solid tumor margin, heterogeneity within the tumor microenvironment, and protection from the blood-brain barrier. Conventional treatments for GBM, such as surgical resection, radiotherapy, and chemotherapy, have shown limited efficacy; therefore, alternate treatments are needed. Tumor chemoresistance and its proximity to critical structures make GBM a prime theoretical candidate for nonthermal ablation with irreversible electroporation (IRE) and high-frequency IRE (H-FIRE). IRE and H-FIRE are treatment modalities that utilize pulsed electric fields to permeabilize the cell membrane. Once the electric field magnitude exceeds a tissue-specific lethal threshold, cell death occurs. Benefits of IRE and H-FIRE therapy include, but are not limited to, the elimination of cytotoxic effects, sharp delineation from treated tissue and spared tissue, a nonthermal mechanism of ablation, and sparing of nerves and major blood vessels. Preclinical studies have confirmed the safety and efficacy of IRE and H-FIRE within their experimental scope. In this chapter, studies will be collected and information extrapolated to provide possible treatment regimens for use in high-grade gliomas, specifically in GBM.