Ultrasound-mediated gene transfer is emerging as a possible alternative to viral gene transfer, and pre-clinical data suggest that it may play a significant role in gene therapy-based approaches to the treatment of disease. As an extracorporeal stimulus, ultrasound can non-invasively and transiently compromise cell membrane permeability (sonoporation), thereby offering the promise of delivering either genes or oligonucleotide-based therapeutics to cells and tissues in a site-specific manner. The membrane-permeabilising effects of ultrasound can be greatly enhanced using microbubble preparations, many of which have, in the past, found application as ultrasound contrast agents. Because these ultrasound-responsive agents are highly amenable to surface modification it has been suggested that they may be exploited as ultrasound-responsive nucleic acid delivery vehicles. In this article we seek to explore the potential role ultrasound, in combination with microbubble-based agents, may play in providing site-specific gene therapy-based approaches for the treatment of cancer.