Histotripsy is a method of ultrasound therapy using very intense, focused sound fields to fragment tissue causing controlled and localized necrosis principally through mechanical actions of cavitation. Highly specialized instrumentation (transducers and electrical drivers) is required to produce these extreme sound fields for research into cavitation physics and therapeutic applications of histotripsy. This paper will describe the evolution of histotripsy instrumentation from the first devices up to the latest phased-array systems with hundreds of channels and transmit-receive capability. While early histotripsy systems used tone bursts generators with limited bandwidth (called “class-D” circuits) for transducer excitation, more recent ones are based on a switched inductor principle to produce shorter duration acoustic emissions. This method has been tested for peak excitation voltages up to 5 kV and 40 A in compact modular systems suitable for phased-arrays. Receive of acoustic signals by the therapeutic array for aberration correction and cavitation mapping is achieved by sensing current generated by the transducer greatly simplifying transmit-receive circuitry while maintaining very large dynamic range. A novel distributed architecture was developed for data handling and signal processing using off-the-shelf FPGA evaluation modules interfaced by ethernet. These latest features will be key to successful clinical translation and widespread adoption of histotripsy.