Small interfering RNA (siRNA) has been demonstrated to be a powerful tool for silencing post-transcriptional gene expression, and thus exhibits great potential in cancer gene therapy. However, siRNA technology has not become an established strategy for cancer treatment, as it is a considerable challenge to deliver siRNA to the targeting sites. In this review, barricades in the systemic delivery of siRNA were systematically introduced, from pharmacokinetics, biodistribution and intracellular behavior. Meanwhile, current and potential strategies for overcoming the barricades were elucidated, including chemical modification of siRNA, nanomaterial-based delivery systems, and targeting and stimuli-responsive smart carriers. In conclusion, the siRNA-based gene silencing drug will gain an important position for treating human diseases if we can solve the gap between ideal and reality.