Abstract The 3-dimensional (3D) conformation of the genome plays a key role in the regulation of gene expression. The development of microscopy, molecular, high-throughput sequencing and computational methods have enabled invesitgations of the 3D architecture of chromatin and the genome. These studies provide views of a hierarchical and dynamic spatial genome topology. Here, I review our knowledge of the organization of chromatin in the eukaryotic nucleus and methodologies for analyzing chromatin architecture in 3D. I address the main current computational 3D genome modeling approaches and resulting biological insights gained from structural genome modeling. Finally, I address perspectives on developments and applications of 3D genome models to better understand healthy and disease states.