Systems, tools and methods are disclosed for the selective and rapid application of DC voltage to drive irreversible electroporation, with the system controller capable of being configured to apply voltages to independently selected subsets of electrodes and capable of generating at least one control signal to maintain the temperature near an electrode head within a desired range of values. Electrode clamp devices are also disclosed for generating electric fields to drive irreversible electroporation while modulating temperature to elevate the irreversible electroporation threshold utilizing a variety of means such as cooling fluid or solid state thermoelectric heat pumps.