Principled approaches from polymer physics are important to make sense of the complexity of experimental data on chromosome 3D architecture and to explain their underlying molecular mechanisms. I discuss first the current picture of the spatial organisation of our DNA across genomic scales at the single cell level, as emerging from technologies such as microscopy, Hi-C, SPRITE or GAM [1]. Next, I discuss how different models of polymer physics can help understanding the origin of the patterns in the data and the underlying folding mechanisms [2,3,4]. Finally, I show that polymer physics can be used to predict the impact of large mutations (Structural Variants) on chromosome structure, in particular on how the network of contacts between genes and regulators is rewired, hence enabling the identification of their pathogenic potential [5,6]. [1] R.A. Beagrie, A. Scialdone, M. Schueler, D.C.A. Kraemer, M. Chotalia, S.Q. Xie, M. Barbieri, I. de Santiago, L.-M. Lavitas, M.R. Branco, J. Fraser, J. Dostie, L. Game, N. Dillon, P.A.W. Edwards, M. Nicodemi*, A. Pombo*, Complex multi-enhancer contacts captured by Genome Architecture Mapping (GAM), a novel ligation-free approach. Nature 543, 519 (2017). [2] A.M. Chiariello, S. Bianco, C. Annunziatella, A. Esposito, M. Nicodemi, Polymer physics of chromosome large-scale 3D organisation, Scientific Reports 6, 29775 (2016). [3] M. Barbieri, S.Q. Xie, E. Torlai Triglia, A.M. Chiariello, S. Bianco, I. de Santiago, M.R. Branco, D. Rueda, M. Nicodemi*, A. Pombo*, Active and poised promoter states drive folding of the extended HoxB locus in mouse embryonic stem cells. Nature Struct. Mol. Bio, 24, 515 (2017). [4] C.A. Brackley, J. Johnson, D. Michieletto, A. N. Morozov, M. Nicodemi*, P. R. Cook*, and D. Marenduzzo*, Nonequilibrium Chromosome Looping via Molecular Slip Links, Phys. Rev. Lett. 108, 158103 (2017) [5] S. Bianco, D.G. Lupiáñez, A.M. Chiariello, C. Annunziatella, K. Kraft, R. Schöpflin, L. Wittler, G. Andrey, M. Vingron, A. Pombo, S. Mundlos*, M. Nicodemi*, Polymer physics predicts the effects of structural variants on chromatin architecture, Nature Genetics 50, 662 (2018). [6] B.K. Kragesteen, M. Spielmann, C. Paliou, V. Heinrich, R. Schoepflin, A. Esposito, C. Annunziatella, S. Bianco, A.M. Chiariello, I. Jerković, I. Harabula, P. Guckelberger, M. Pechstein, L. Wittler, W.-L. Chan, M. Franke, D.G. Lupiáñez, K. Kraft, B. Timmermann, M. Vingron, A. Visel, M. Nicodemi*, S. Mundlos* and G. Andrey*, Dynamic 3D Chromatin Architecture Determines Enhancer Specificity and Morphogenetic Identity in Limb Development, Nature Genetics 50, 1463 (2018).