In vivo gene silencing using RNAi plays an important role in target validation and is advancing towards the development of RNAi-based therapeutics. RNAs were thought to have just two broad functions in cells as messenger RNAs (mRNAs) and ribosomal RNAs, but recently the relevance of microRNAs is becoming more clearly understood. mRNA molecules transmit information between DNA and protein and, as such, are vital intermediaries for gene expression. Ribosomal and transfer RNAs have structural, catalytic, and information-decoding roles in the process of protein synthesis, whereas microRNAs are regulators of gene expression. This review presents the early and intriguing successes of using siRNAs for in vivo gene silencing and its use as a possible cancer therapeutics. J. Cell. Physiol. 220: 285–291, 2009. © 2009 Wiley-Liss, Inc.