<p>Nanoscale chromatin domains have emerged as fundamental units of mammalian genome organization during interphase and mitosis. Single-molecule localization microscopy now enables their direct visualization, revealing conserved features including characteristic packing, enrichment of linker histones, and radial stratification of histone marks. These domains act as dynamic regulators of gene activity, remodel in response to developmental and environmental cues, and become disrupted in disease. Experimental findings and biophysical modelling point to internucleosomal interactions and epigenetic reactions as key drivers of their organization. By situating them alongside lamin- and nucleolus-associated domains, we propose a unified biophysical framework for genome organization across scales. Their recurrent disruption in aging and disease makes them compelling targets for diagnosis and intervention.</p>