Cancer gene therapy remains a promising approach to treating a variety of malignancies by inducing tumor cells to generate gene products that kill cancer cells without hurting healthy tissue. However, cancer gene therapy, as well as gene therapy for other diseases, has been restricted by the difficulty of safe and effective delivery of DNA into the cytoplasm of tumor cells. There are basically two main barriers to overcome. The first is the lack of effective means of systemic targeting, i.e., targeted delivery of the injected DNA to the tumor and homogeneous accumulation throughout the tumor tissue. The second is the poor control of intracellular targeting, i.e., transport of DNA to the nucleus, where it can be transcribed. In this issue, two new important developments to overcome these barriers using ultrasound-guided targeting with microbubbles are described to facilitate cancer gene therapy.