Methods and devices for producing cavitation in tissue are provided. In one embodiment, a low-frequency ultrasound pulse is transmitted into tissue, a high-frequency ultrasound pulse is transmitted into tissue, and a composite waveform is formed in the tissue that has a peak negative pressure value that exceeds an intrinsic threshold for cavitation in the tissue. In some embodiments, the peak negative pressures of the individual ultrasound pulses do not exceed the intrinsic threshold for cavitation. In another embodiment, a plurality of ultrasound pulses at various resonant frequencies are transmitted into tissue, and the time delays between these transmissions are adjusted to allow the ultrasound pulses to align temporally and form a monopolar pulse having a compound peak negative pressure that exceeds an intrinsic threshold for cavitation in the tissue. Systems for performing Histotripsy therapy are also discussed.
