Chemically synthesized siRNAs are widely used for gene silencing. For in vitro applications, stability, delivery, and immunological issues are rarely problematic, but for in vivo applications the situation is different. Limited stability, undesirable pharmacokinetic behaviour, and unanticipated side effects from the immune system call for more careful structural siRNA design and inclusion of chemical modifications at selected positions. Also the notion that siRNA induces significant off-target silencing of many non-related genes has promted new effective measures to enhance specificity. The scope of this review is to provide a simple guide to successful chemical and structural modification of siRNAs with improved activity, stability, specificity, and low toxicity.