The major feature that stands out in the nucleus of all metazoan genomes are the chromosome territories (CTs), which have nonrandom radial positions that are conserved through evolution. We are using our custom Oligopaint FISH probes to identify signatures of chromosome arrangement across different cell cycle stages, tissues, and developmental time points in both Drosophila and mammalian cells. Our experiments allow us to integrate levels of chromatin compaction, chromosome intermingling, and the epigenetic state of large domains in a single-cell and genome-wide manner. Using this approach, we are dissecting the contributions of putative architectural proteins to the radial positioning and folding of chromosomes as well as their function in genome integrity.