The prospect of introducing siRNA in a cell, to induce silencing of the corresponding gene, has encouraged research into RNAi-based therapeutics as treatment for human diseases. At present, the siRNA molecules that are in a more advanced stage of clinical evaluation have a common factor: all are delivered locally at the site of the disease. Thus, the state of the art in delivery of siRNA appears to be the local administration. This can certainly be attributed to the characteristics of siRNA molecules, such as relatively high molecular weight, negative charge, and susceptibility to nuclease degradation, which make systemic application as a drug molecule difficult. When focusing on local administration, the main concerns for siRNA delivery can be restricted to the trafficking of siRNA molecules from the vicinity of the target cells, to the intracellular compartment where RNAi takes place, i.e. the cytoplasm. This contribution is focused on the barriers and challenges in trafficking of siRNA upon local delivery. First, an overview is given on the current state of the art for siRNA delivery in clinical trials. Second, recent successful preclinical studies, involving direct and local administration of siRNA, are reviewed. Third, emphasis is given to the endosomal escape. Some of our recent work is presented: the application of photochemical internalization (PCI) to improve the endosomal escape of siRNA lipoplexes in vivo. Finally, concluding remarks focus on the advantages of employing a technique such as PCI to enhance the endosomal escape of siRNA molecules.