The field of gene therapy has experienced some success in the past decade. However, overall, gene therapy clinical trials have been challenging due to low transduction efficiency and low transgene expression. To overcome these obstacles, drug-resistance gene therapy provides an alternative to enrich gene-modified cells and enhance transgene expression. In this chapter, we present an overview of current gene-resistance gene therapy and different mechanisms of drug resistance that have been used in the selection of gene-modified cells. Although the first clinical applications are concentrated in cancer applications, the technology may be widely applicable. Finally, we also describe using this technique for the treatment of human gliomas.