RNAi is a ubiquitous and highly specific, endogenous, evolutionarily conserved mechanism of gene silencing. RNAi holds great promise as a novel therapeutic modality. Despite the rapid progress in the understanding and utilization of RNAi in vitro, the application of RNAi in vivo has been met with great difficulties, mainly in the delivery of these molecules into specific cell types. Here, we describe the major systemic nanomedicine platforms that have been developed. Focus is given to the development of new strategies to target subsets of leukocytes, which are among the most difficult cells to transduce with RNAi. Finally, we discuss the hurdles and potential opportunities for in vivo manipulation of the immune response utilizing RNAi nanomedicines.