RNA interference (RNAi) is a powerful tool for gene silencing. Over the past decade our increased understanding of the molecular mechanisms underlying RNAi has provided an avenue towards utilizing it therapeutically. Of the many RNAi precursors, small interfering RNAs (siRNAs) have been the most successfully translated into the clinic. One of the major issues with RNA-based medicines is the cells’ ability to see and respond via pattern-recognition receptors such as Toll-like receptors (TLRs) and retinoic acid inducible gene 1 (RIG-1), inducing innate and adaptive immune responses. We propose that in certain diseases the combination of gene silencing and appropriate immune activation by so-called ‘bifunctional siRNA’ is a rational therapeutic approach and worthy of further investigation. Here we briefly review the progress in developing siRNA-based therapeutics and its interaction with the immune system, including siRNA design, types of immune activation, RNAi use in cancer and viral infections, as well as pre-clinical applications. We believe that development of immunostimulatory siRNAs provides the means for more potent therapies.