The discovery of novel nucleic acid folding architectures bears a twofold interest related to the structural properties of unprecedented forms and to their functional significance. In addition, physiologically and pathologically important processes can be impaired by endogenous or xenobiotic ligands interacting with specific target sequences. In this paper we will focus on recent advances in the study of telomeric G-quadruplex DNA and RNA structures and the rational design and development of synthetic ligands aimed at pharmacological applications.