An extreme folding dynamics of G4s, as observed here, is certain to impact and possibly modulate their interaction with proteins (59,60) and ligands (61). Although the majority of observed folded states are only marginally stable in current conditions, we expect that they can be individually recognized and trapped through selective structure-specific interactions with different ligands (62) and proteins (63). The structural knowledge available through our experiments can potentially be used to control the folding pathway of G4 structures, i.e. through stabilization of particular G4 conformations via specifically tailored G4-ligand interactions. Therefore, this extreme folding dynamics of G4s should be considered for the development of novel G4-targeting anti-cancer therapies and for elucidating G4-proteins interactions. Our work thus provides a comprehensive thermodynamic and kinetic description of the folding of telomeric G4s, the implications of which may contribute to the structural and energetics framework necessary for future studies of G4 folding in vivo.