Irreversible electroporation (IRE) is a promising technology to treat local malignant cancer using short, high-voltage electric pulses. Unfortunately, in vivo studies show that IRE suffers from an inability to destroy large volumes of cancer tissue without introduction of cytotoxic agents and/or increasing the applied electrical dose to dangerous levels. This research will address this limitation by leveraging membrane-targeting mechanisms that increase lethal membrane permeabilization. Methods that directly modify membrane properties or change the pulse delivery timing are proposed that do not rely on cytotoxic agents. This work shows that significant enhancement (67-75% more cell destruction in vitro and >100% treatment volume increase in vivo) can be achieved using membrane-targeting approaches for IRE cancer destruction. The methods introduced are surfactants (i.e., DMSO) and pulse timing which are low cost, non-toxic, and easy to be incorporated into existing clinical use. Moreover, when needed, these methods can also be combined with electrochemotherapy to further enhance IRE treatment efficacy.