The main challenges for application of gene therapy to patients are poor selectivity in vector targeting, insufficient gene transfer, and great difficulties in systemic treatment in association with safety concerns for particular vector systems. For success in gene therapy, safe, applicable, and efficient transfer technologies are required. Because of the complex nature of targeted vector delivery to the tumor, our strategy for gene therapy is focused on the development of local nonviral gene transfer. This approach of local interference with tumor growth and progression could contribute to better control of the disease. Transfer of naked DNA is an important alternative to liposomal or viral systems. Different physical procedures are used for improved delivery of naked DNA into the target cells or tissues in vitro and in vivo. Among the various nonviral gene delivery technologies, jet-injection is gaining increased attractiveness, because this technique allows gene transfer into different tissues with deep penetration of naked DNA by circumventing the disadvantages associated with, e.g., viral vectors. The jet-injection technology is based on jets of high velocity for penetration of the skin and underlaying tissues, associated with efficient transfection of the affected area. The jet-injection technology has been successfully applied for in vivo gene transfer in different tumor models. More importantly, the efficacy and safety of jet-injection gene transfer have recently been investigated in a phase I clinical trial.