Aim and Background .RNA interference has the role of gene silencing process that is triggered by double-stranded RNAs. Common to all cell types, is the production of 21-24 nucleotide small interfering RNA (siRNA), which guides the RNA-induced silencing complex (RISC) to identify and cleave target mRNA sequences. siRNA duplex are potent activators of innate immune system that induce high levels of cytokines and interferon. Toll-like receptors trigger the first line of innate immune response that is mediated by transcriptional induction of a large number of cellular genes. siRNA interact with cytoplasmic RNA sensors such as: Retinoic - acid Inducible Gene -I (RIG-I), RNA-Activated protein kinase R(PKR), Interferon Regulatory Factor (IRF) and 2'-5' oligo adenylate synthetase (2'-5'OAS), Nuclear Factor kappa B cell(NF-κB). siRNA modification are on the sugar, phosphate linkage, base, overhangs and termini nucleotides leading to increase half-life siRNA. This review article describes gene silencing and innate immune caused by siRNA.