TRAIL (tumor necrosis factor-related apoptosis-inducing ligand),also known as APO2L,belongs to the tumor necrosis factor family.By binding to the death receptor 4 (DR4) or DR5,TRAIL induces apoptosis of tumor cells without causing side toxicity in normal tissues.In recent years TRAIL-based therapy has attracted great attention for its promise of serving as a cancer drug candidate.However,the treatment efficacy of TRAIL protein was under expectation in the clinical trials because of the short half-life and the resistance of cancer cells.TRAIL gene transfection can produce a "bystander effect" of tumor cell killing and provide a potential solution to TRAIL-based cancer therapy.In this review we focus on TRAIL gene therapy and various design strategies of TRAIL DNA delivery including non-viral vectors and cell-based TRAIL therapy.In order to sensitize the tumor cells to TRAIL-induced apoptosis,combination therapy of TRAIL DNA with other drugs by the codelivery methods for yielding a synergistic antitumor efficacy is summarized.The opportunities and challenges of TRAIL-based gene delivery and therapy are discussed.