In 1953, Watson and Crick proposed that canonical DNA is a double-helical structure and not a triple helix as was a predominant theory prior . In the ensuing years, however, Hoogsteen and other crystallographers observed purines binding their complement from a different side of the base than predicted by Watson and Crick, in a different conformation . Questions surrounding the preferred bonding scheme of adenine in particular were not definitively answered until 1973 . Nowadays, these uncertainties are largely forgotten and the canonical secondary structure of DNA is mostly as Watson and Crick predicted: a double helix stabilized by two specific base pairs. However, fascinating recent discoveries have revealed that genomic DNA is much more structurally diverse than what is evident from the Watson-Crick (WC) model alone. Hoogsteen (HS) base pairs are abundant in the genomes and transcriptomes of all organisms, especially eukaryotes; as many as 0.2-1.2% of base pairs in canonical B-form DNA transiently exists as a HS base pair . Additionally, triple-helical DNA, which is formed when purines pair simultaneously from both their WC and HS interfaces, is overrepresented in regulatory regions of chromosomes and has been implicated in various key biological processes . Intriguingly, it has recently been proposed that long noncoding RNA strands contribute to large-scale three-dimensional organization of the human genome via triplex formation .