Tissue destruction by lithotripter shock-wave-induced cavitation can be effective for antitumor therapy. Since DNA transfection can be accomplished through cavitation-induced sonoporation, the potential may exist for an advantageous combination of shock wave and gene therapy of tumors. B16 mouse melanoma cells were cultured by standard methods and a luciferase reporter vector was used as the DNA plasmid. The shock-wave generation system, similar to a Dornier HM-3 lithotripter, had peak pressure amplitudes of 24.4 MPa positive and 5.2 MPa negative. In vitro exposures of cell suspensions indicated that results were greatly enhanced by leaving an air space in the exposure chambers to promote cavitation activity. For in vivo exposure, cells were implanted subcutaneously in C57BL/6 mice 10–14 days before treatment. DNA at 0.2 mg/ml and sometimes air at 10% of tumor volume was injected intratumorally before exposure. Exposure to 800 shock waves, followed by culture of isolated tumor cells for one day, yielded 1.1 (0.43 SE) pg luciferase production per 106 cells, increasing to 7.5 (2.5 SE) pg/106 cells for air injection. Significant luciferase production occurred for 200, 400, 800, and 1200 shock waves with air injection. Gene transfer therefore can be induced during lithotripter shock-wave treatment of tumors. [Work supported by NIH Grant No. CA42947.]