RNA interference mediated by short interfering RNA is widely used to study functional genes and also being developed for therapeutic applications. However, recent study demonstrated that siRNA might activate innate immune system and induce huge production of inflammatory cytokines in mammals, and also randomly inhibit expression of undesired genes. Designing highly effective siRNAs or modifying the siRNA to retain or enhance the silence efficiency and meanwhile abolish the off-target effects associated with immunostimulation then become the key techniques in application of siRNAs as safe and effective therapeutic agents.