Gene therapy is an exciting novel approach for treating cancers resistant to currently available modalities. Treatment approaches are based on taking advantage of molecular differences between normal and tumor cells. Various strategies are currently in clinical development, with some promising early results reported with mutation compensation, molecular chemotherapy and replication competent viruses. Adenoviruses are among the most popular vehicles and there is a wealth of clinical data suggesting excellent safety for treatment of cancer patients. Current developments include improving targeting strategies for gene delivery to tumor cells with tumor specific promoters. Another rapidly developing field is replication competent agents, which allow improved tumor penetration and local amplification of the anti-tumor effect. Further, infectivity enhancement strategies can overcome variable expression of the primary adenovirus receptor on tumor cells, which may have reduced the clinical efficacy of previous strategies. Adenoviral cancer gene therapy approaches lack cross-resistance with other treatment options and frequently synergistic effects can be observed. Therefore, the first routine clinical applications are likely to be combination treatments.