Efficient delivery of siRNA to cancer cells after systemic administration poses a significant challenge. While many methods of nucleic acid delivery have been described, encapsulation of siRNA in lipid nanoparticles (LNPs) represents the most clinically advanced delivery approach. Currently, there are two siRNA-LNP-based treatments (ALN-VSP and TKM-PLK1) in clinical trials targeting solid tumors, with additional studies ongoing for noncancer diseases. The consensus from these clinical studies is that siRNA-LNP represents safe and potent silencing systems. Improvements in LNP technology through development of more potent and biocompatible ionizable cationic lipids along with targeting lipids to mediate delivery of LNPs specifically to cancer cells are on the horizon. In combination with genomic screening, it is possible that within the next 5 years the pathogenic drivers of individual cancers will be identified and siRNA-based personalized medicines will be formulated to achieve successful treatment of cancer and other genetic diseases.