The elementary level of chromatin fiber, namely the nucleofilament, is known to undergo a hierarchical compaction leading to local chromatin loops, then chromatin domains and ultimately chromosome territories. These successive folding levels rely on the formation of chromatin loops ranging from few kb to some Mb. In addition to a packaging and structural role, the high-order organization of genomes functionally impacts on gene expression program. This review summarises to which extent each level of chromatin compaction does affect gene regulation. In addition, we point out the structural and functional changes observed in diseases. Emphasis will be mainly placed on the large-scale organization of the chromatin.