Short interfering RNAs (siRNA) are routinely used in the laboratory to induce targeted gene silencing by RNA interference, and increasingly, this technology is being translated to the clinic. However, there are multiple mechanisms by which siRNA may be recognized by receptors of the innate immune system, including both endosomal Toll-like receptors and cytoplasmic receptors. Signaling through these receptors may induce multiple nonspecific effects, including general reductions in gene expression and the production of type I interferons and inflammatory cytokines, which can lead to systemic inflammation in vivo. The pattern of immune activation varies depending upon the types of cells and receptors that are stimulated by a particular siRNA. Although we are still discovering the mechanisms by which these recognition events occur, our current understanding provides useful guidelines for avoiding immune activation. In this minireview, we present a design-based approach for developing siRNA-based experiments and therapies that evade innate immune recognition and control nonspecific effects. We describe strategies and trade-offs related to siRNA design considerations including the choice of siRNA target sequence, chemical modifications to the RNA backbone and the influence of the delivery method on immune activation. Finally, we provide suggestions for conducting appropriate controls for siRNA experiments, because some commonly employed strategies do not adequately account for known nonspecific effects and can lead to misinterpretation of the data. By incorporating these principles into siRNA design, it is generally possible to control nonspecific effects, and doing so will help to best utilize this powerful technology for both basic science and therapeutics.