The less of high efficient carriers to deliver siRNA drugs into their targeted tissues/cells with less toxicity are the major obstacles of siRNA pharmaceuticals in clinic application. The recent advance of siRNA delivery research based on cell-penetrating peptides (CPPs) in clinic opened the way of siRNA techniques for therapeutic application (Yi et al., Mol Ther (2011)19, 362-371). CPPs are short amphipathic and cationic peptides that are rapidly internalized across cell membranes. They can be used to deliver molecular cargos, such as imaging agents (fluorescent dyes and quantum dots), drugs, liposomes, peptide/protein, oligonucleotide/DNA/RNA, nanoparticles and bacteriophage into cells. The mechanism of cellular uptake and subsequent processing still remains controversial. It is now clear that CPP can mediate intracellular delivery via both endocytic and non-endocytic pathways. In this review, we discuss potential functions of CPPs, especially in structure modified CPPs for small RNA delivery in vitro and in vivo, highlighting their powerful promise for clinical efficacy.