A key barrier to the development of gene therapy remains the lack of safe, efficient and easily controllable vehicles for gene delivery. The fundamental problems associated with the viral vehicles, e.g. lack of specificity and immunogenic potential, have driven the development of non-viral systems of gene delivery. In the last decade, studies on p53 gene replacement therapy have dominated the literature. Although clinical trials of p53 gene therapy have achieved limited success, it remains the only tumor suppressor gene to be evaluated formally in clinical trials for cancer treatment, with increasing focus on delivery using non-viral systems. In this article, we particularly review current investigations on p53 gene delivery using non-viral methods, including both physical and chemical approaches, with an emphasis on the latter. The existing opportunities and challenges for successful p53 cancer gene therapy are also discussed.