Gene therapy, which involves replacement of a defective gene with a functional, healthy copy of that gene, is a potentially beneficial cancer treatment approach particularly over chemotherapy, which often lacks selectivity and can cause non‐specific toxicity. Despite significant progress pre‐clinically with respect to both enhanced targeting and expression in a tumor‐selective manner several hurdles still prevent success in the clinic, including non‐specific expression, low‐efficiency delivery and biosafety. Various innovative genetic approaches are under development to reconstruct vectors/transgenes to make them safer and more effective. Utilizing cutting‐edge delivery technologies, gene expression can now be targeted in a tissue‐ and organ‐specific manner. With these advances, gene therapy is poised to become amenable for routine cancer therapy with potential to elevate this methodology as a first line therapy for neoplastic diseases. This review discusses recent advances in gene therapy and their impact on a pre‐clinical and clinical level. J. Cell. Physiol. 230: 259–271, 2015. © 2014 Wiley Periodicals, Inc.