The present invention is directed to compositions comprising chemically modified siRNA that have high specificity by virtue of no or insignificant off-target activity of the sense strand, no or insignificant induction of IFN-like responses, high potency to offset oligonucleotide manufacturing costs, favorable manufacturing chemistry, and effective means of intracellular delivery both in vitro, during target validation and model studies, and in vivo, during animal model studies and clinical trials in humans.