One reason for the problem with intracellular trafficking of oligonucleotides arises from the mode carrier/cargo complexes are taken up by cells. Today it is well established that the majority of these complexes are taken up via endosomal pathways and therefore end up in vesicular compartments from which they have to escape in order to reach their target. Although there are many attempts reported to trigger endosomal escape by various strategies, they either proved to be toxic or did not achieve sustained success. Additionally, there might be a further reason for the encountered difficulties to overcome these intracellular barriers. It is not unreasonable to speculate that during evolution cells might have evolved mechanisms to avoid large amounts of foreign nucleic acids freely floating in the cytoplasm and thus safely contain them in vesicular compartments where they are eventually degraded. Alternatively they might be exported by retrograde transport. Co-evoluting viruses evidently have developed strategies to circumvent such defense mechanisms. So it might be somewhat naive to expect that a rather simple man-made carrier system is capable to efficiently overcome such an intrinsic barrier. Current developments towards more complex and elaborate carrier systems take into account such considerations. In any case it appears there is no simple solution for this problem.