RNA interference (RNAi) is a general term used for various strategies to interfere with the expression of a target protein at the post-transcriptional stage, either by degrading the mRNA responsible for the synthesis of the protein or blocking the translational access to the mRNA. RNAi has spurred intense interest in research community for its potential as a tool in addressing specific scientific questions as well as its therapeutic potential in a clinical setting. RNAi can be undertaken by employing a variety of mediators, including short interfering RNA (siRNA), the focus of this chapter. Here, we examine different applications of protein silencing via siRNAs, review the intracellular and extracellular barriers for effective siRNA delivery, present (and analyze) various delivery systems used to overcome these barriers, and assess some of the recent achievements in the field. Considering the prominent role of cancer therapy in siRNA research and development, we focus our examples and analysis on this disease. Delivery issues surrounding effective use of siRNA are emphasized and we conclude this chapter with select examples of unconventional delivery approaches employed for siRNA.