The presence of folded regions in RNA competes with the binding of a complementary oligonucleotide, resulting in a weak antisense effect. Due to the key role played by a number of RNA structures in the natural regulation of gene expression it might be of interest to design antisense sequences able to selectively interact with such motifs in order to interfere with the biological processes they mediate. Different possibilities have been explored. A high affinity oligomer will disrupt the structure; if the target structure is solved one can take advantage of unpaired bases (bulges, loops) to minimize the thermodynamic cost of the binding. Alternatively, the folded structure can be accommodated within the complex via the formation of a local triple helix. Oligomers able to adapt to the RNA structure (aptamers) can be extracted by in vitro selection from randomly synthesized libraries comprising several billions of sequences.