Targeting the specific genetic lesions responsible for carcinogenesis and cancer progression is an attractive strategy for developing more effective anticancer therapeutics and reducing treatment-related toxicity. The restoration of defective tumor suppressor gene pathways by replacement of tumor suppressor genes in cancer cells has been studied in lung cancer and head and neck cancer (HNC). The most extensively studied agent is the wild-type p53 tumor suppressor gene delivered by an adenoviral vector. Clinical trials to date in non-small cell lung cancer and HNC have consistently shown evidence of gene transduction and expression, mediation of apoptosis, and clinical responses including pathological complete responses. It is also clear, however, that this approach can be improved further. Promising avenues for investigation include improved gene delivery systems, induction of bystander effects, design of immunogene and antiangiogenesis gene therapies, and adjuvant use of gene therapy with conventional chemotherapy, radiation therapy, and surgery. These strategies, however, will need further refinement to succeed clinically. This review examines several important issues in cancer gene therapy in general and the most recent achievements in gene therapy for HNC and non-small cell lung cancer.