The diameter of a mammalian nucleus is thousands of times shorter than the length of the fully-stretched genomic DNA that it hosts.This fundamental spatial constraint leads to a complex compaction of the genomic DNA into chromosomes, which occupy discrete positions in the nucleus.Although our understanding of the physical and spatial organization of genomes remains largely incomplete, a decade of rapid method development has begun to yield exciting insights into the three-dimensional (3D) architecture of mammalian genomes.The specifics of this 3D organization set the physical landscape of a genome and have been demonstrated to play important roles in cellular and developmental events.Defects in genome architecture might also lead to human diseases, including cancer.