The innate immune system uses pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) to recognize conserved pathogen-associated molecular patterns (PAMPs) expressed by microbes and to activate the initial phase of immune response. Both bacterial and viral nucleic acids activate TLRs resulting in cytokines and interferon production. Recent studies indicated that unmodified small interfering RNAs (siRNAs) corresponding to either mammalian (self) or microbial (non-self) RNA sequences can activate immunity through TLR7/8 in a sequence-dependent manner. Hence, the use siRNAs in humans will require understanding the mechanisms involved in the discrimination between self and non-self RNAs. In the case where immunostimulation is not wanted, chemical modifications can prevent immune activation and reduce off-target effects, while preserving siRNA silencing potency. Interestingly, 2'-O-methyl modified RNAs not only evade immune sensing, but antagonize with immunostimulatory single- or double-stranded siRNAs to activate innate immunity. This review highlights the recent progress in understanding the siRNA sensing by innate immunity and presents a range of strategies allowing either the design of siRNAs with minimal or maximal immunostimulatory potency for therapeutic applications.