Purpose: Lung cancer carries a dismal prognosis with conventional therapies achieving no significant improvements in survival in the last decade. In recent years, the advances achieved in understanding the molecular biology of cancer have afforded clinicians and scientists the opportunity to develop a range of novel genetic therapies for this disease. Materials and Μethods: A detailed review of the published reports dealing with gene therapy of lung cancer has been conducted. Particular emphasis has been placed on recent developments in the arena of non-viral (plasmid DNA, DNA-coated gold particles, liposomes and polymer-DNA complexes) and viral (adenovirus, retrovirus, adeno-associated virus, herpes virus and pox virus) vectors. Therapeutic strategies were categorised as corrective, cytoreductive and immunomodulatory gene therapy for the purpose of data analysis and comparison. Results: Loco-regional administration of both non-viral and viral vectors can yield impressive local gene expression and therapeutic effects but, as yet, no efficient systemically-delivered vector is available. Corrective gene therapy to restore normal patterns of tumor suppressor gene (p53, Rb, p21, p16) expression or to negate the effect of mutated tumor promoting oncogenes (ras, myc, erbB2, bcl-2) have efficacy in animal models but this approach suffers from the fact that every cancer cell must be targeted. A wide variety of cytoreductive strategies are under development, including suicide, anti-angiogenic, radioisotopic and pro-apoptotic gene therapies. Each of these approaches has strengths and weaknesses and may best be suited to use in combination. Immunomodulatory gene therapy seeks to generate an effective local immune response which translates to systemic antitumor activity. At present, most studies employ immunostimulatory cytokine genes (GM-CSF, IL-2, IL-12). Conclusions: A variety of therapeutic genes have proven activity against lung cancer in vitro and in vivo. However, the chief challenge facing clinical gene therapy strategies is the lack of efficient gene delivery by local and systemic routes and, for the foreseeable future, vector development will remain a major focus of ongoing research. Despite this caveat, it is anticipated that gene therapy approaches will make a significant contribution to the management of lung cancer in the future. Pneumon 2002, 15(1):19-37.