In recent years, the development of gene therapy systems as new treatment or prevention strategies for various malignant diseases has been explored. Based on the genetic background of esophageal cancer, several molecular therapies have been developed. In this article, we review p53 genetic alterations and angiogenesis in esophageal cancer. Our recent clinical results from a phase I/II study of adenoviral-mediated p53 gene therapy for patients with un-resectable esophageal cancer are reviewed. Lastly we review the available experimental therapeutic models from the literature and our experimental work over the past few years are reviewed.