Within the nucleus, genomic DNA is exquisitely packaged with proteins creating highly folded yet dynamic fibers of chromatin. A fundamental biomedical question is how this folding is organised and regulated to ensure cell identity and survival, however, the current paradigm of genome organisation is still primitive as it does not address the existence of non-canonical DNA structures. Heterochromatin Protein 1α (HP1α) is a major architectural protein that organises the genome into highly compact domains of heterochromatin, thus preventing access to certain genomic locations. Dysregulation of heterochromatin has been implicated in cancer and ageing. We have recently observed that HP1α interacts strongly with specific non-canonical nucleic acid structures. Therefore, we hypothesise that these interactions are key determinants of heterochromatin architecture and will employ structurally sensitive techniques to propose a new molecular model of heterochromatin formation; a model that will transform studies in areas such as cancer biology and regenerative medicine.