DNA vector-based short hairpin RNA (shRNA) as a means of effecting RNA interference (RNAi) is a promising mechanism for the precise disruption of gene expression to achieve a therapeutic effect. The clinical usage of shRNA therapeutics in cancer is limited by obstacles related to effective delivery into the nuclei of target cancer cells. Significant pre-clinical data have been amassed about biodegradable and non-biodegradable polymeric delivery vehicles that are relevant for shRNA delivery into humans. Here, we will review some leading candidates for clinical usage with a focus on studies relating to their potential for usage in cancer shRNA therapeutics and discuss some of the advantages and disadvantages of using biodegradable and non-biodegradable delivery vehicles.