Gene silencing based on RNA interference (RNAi) has been a common trait of certain pathogen and pest-resistant commercial, genetically modified (GM) crops. More recently, sprayable dsRNA-based crop protection agents have started maturing toward commercialization, with one product against Colorado potato beetles in potato crop authorized in the USA. As this chemistry is entirely different from the mainstream conventional pesticides, questions arise as to how their safety should be assessed, particularly in light of the perceived low concerns. This chapter reviews the experience already gained with RNA-based products in sprayable pesticides, GM crops, hypovirulent dsRNA mycoviruses used in forestry, pepinoviruses used in crop protection, and dsRNA used in cosmetics. Based on their commonalities, a strategy of dsRNA safety assessment might involve considerations of target specificity, exposure of consumers and non-target organisms (NTOs), and the safety of co-formulants and impurities, as well as their impact on dsRNA safety.