Radiotherapy is a widely used treatment for localized malignancies that is often delivered in combination with cytotoxic chemotherapeutic agents. The concept that treatment of localized tumors can be improved with a radio- and chemo-inducible gene therapy strategy has been investigated in the laboratory and now translated to the clinic. The TNFerade (Ad.Egr-TNF11D) adenoviral vector was engineered by inserting radio- and chemo-inducible elements from the Egr-1 promoter upstream to a cDNA encoding tumor necrosis factor-alpha (TNF-alpha). Transduction of tumor cells with TNFerade and then treatment with radiation or chemotherapy is associated with spatial and temporal control of TNF-alpha secretion and enhanced antitumor activity. TNFerade has been evaluated in trials for patients with sarcomas, melanomas and cancers of the pancreas, esophagus, rectum and head and neck. If the ongoing phase III trial for pancreatic cancer is successful, TNFerade will likely become the first gene therapy approved for cancer in the United States.