The ability to specifically silence genes using RNA interference (RNAi) has wide therapeutic applications for the treatment of disease. Numerous studies have demonstrated global gene and protein signatures distinguishing malignant and nonmalignant tissues. This worldwide pursuit of optimal cancer targets has so far provided a wide list of potential targets for each cancer type and for each patient, for which RNAi-based therapies can be applied. Nevertheless, due to poor stability of RNAi molecules in physiological conditions and their inability to cross cellular membranes, the delivery of siRNA and microRNA (miRNA) in vivo holds a great challenge and remains a crucial issue for their therapeutic success. Supramolecular carriers are often used in order to improve the physicochemical and biopharmaceutical properties of RNAi. Nano-sized delivery systems enable the accumulation of drugs and oligonucleotides (ONTs) in angiogenesis-dependent areas due to the enhanced permeability and retention (EPR) effect, and are able to cross cellular membranes and release the siRNA/miRNA only inside the target cell. In addition, a targeting moiety can increase the selectivity and specific uptake in the target tissue. Several vehicles (dendrimers, nanoparticles, liposomes, polyplex, lipoplex, polymeric nanoconjugates) are being developed for siRNA/miRNA delivery. These vehicles provide an important tool for exploiting the full potential of ONTs as therapeutic agents. In this review we will focus on the polymer-based approaches to deliver siRNA to cancer in vivo.