Abstract: Irreversible Electroporation (IRE) is a minimally invasive surgical therapy we invented to treat unresectable tumors using low-energy microsecond pulses. IRE is unique among tissue ablation techniques in affecting only the cell membrane while tissue molecules, everything encompassing collagen structures to proteins; remain intact, thereby making treatment near critical structures such as major blood vessels and nerves possible. This form of cancer therapy received the Expedited Pathway Designation in 2018 and has been used to help thousands of patients worldwide. We are developing an advanced form of the technology, high frequency irreversible electroporation (HFIRE) for the treatment of glioblastoma (GBM). This new therapy preferentially targets cancer cells over healthy cells, transiently disrupts the blood-brain barrier for delivery of therapeutics, and induces a positive immune response. Our preclinical work focuses on helping canine patients with naturally occurring GBM, which are excellent translational models of human GBM. Results of our ongoing trials have been extremely positive, supporting that HFIRE is effective for the treatment of GBM, including tumors refractory to surgery, radio- and chemotherapies.