The enormous promise of siRNA technology for rational and targeted therapy can only be realized if the inherent problems in terms of pharmaceutical development are overcome. Besides liposomal and polymeric nanoparticles, fusion proteins hold great potential for cell-type specific delivery of siRNA. Consisting of a protein binder and an oligonucleotide complexing domain, fusion proteins are designed for targeted delivery to a certain tissue or organ and subsequent release of the siRNA after cellular uptake. This article focuses on the possibilities and importance of targeting and complexing domains, including polymers and dendrimers. In vitro and in vivo evaluations are discussed with an in-depth view on pharmacokinetic properties. Remaining challenges concerning specificity on the tissue and molecular levels are highlighted.