Clinical applications of antisense oligonucleotides depend on the development of suitable transfer vehicles. In this regard, liposomes are of potential interest because they are made of phospholipids which are natural constituents of all cell membranes; thus toxicity is not expected to be a problem. Phospholipids may organize or disorganize at a supramolecular level depending on their nature and the microenvironment. This allows the production of ‘intelligent’ vesicles which are able to fuse, aggregate, leak or turn into other supramolecular organizations at a given pH, temperature or ionic strength. In addition, liposomes are very versatile carrier systems since they can be prepared in various sizes, morphologies, compositions and surface charges, and they can be tailored to the application needed. Finally, they may be functionalized with antibodies, lectins or hydrophilic polymers such as polyethyleneglycol in order to modify their cell and/or tissue distribution. Since the effectiveness of antisense oligonucleotides is limited by a low efficiency of cellular uptake (see also Chapter 9) and the lack of stability due to degradation by nucleases, their incorporation into liposomes has been considered to improve their transfer and delivery into cells. Most liposomes used for this purpose are cationic liposomes which form stable complexes with the polyanionic oligonucleotides. However, more sophisticated liposomal systems have been considered, such as pH-sensitive liposomes which can improve the endosomal escape of oligonucleotides after endocytosis, or immunoliposomes, which can deliver these molecules intracellularly through a receptor-mediated endocytosis. Plasma or lysosome membrane fusion may also be obtained through the use of virus-derived liposomes. This chapter will focus on the advantages and disadvantages of the different strategies using liposomes for oligonucleotide delivery.