Well over a hundred reports have been published describing use of synthetic small-interfering RNAs (siRNAs) in animals. The majority of these reports employed unmodified RNA duplexes. While unmodified RNA is the natural effector molecule of RNA interference, certain problems arise with experimental or therapeutic use of RNA duplexes in vivo, some of which can be improved or solved through use of chemical modifications. Judicious use of chemical modifications can improve the nuclease stability of an RNA duplex, decrease the likelihood of triggering an innate immune response, lower the incidence of off-target effects (OTEs), and improve pharmacodynamics. This review will examine studies that document the utility of various chemical modifications for use in siRNAs, both in vitro and in vivo, with close attention given to reports demonstrating actual performance in animal model systems.