The organization of the genome into topological domains (TADs) appears to be a fundamental process occurring across a wide range of eukaryote organisms, and it likely plays an important role in providing an architectural foundation for gene regulation. Initial studies emphasized the remarkable parallels between TAD organization in organisms as diverse as Drosophila and mammals. However, whereas CTCF/cohesin loop extrusion is emerging as a key mechanism for the formation of mammalian topological domains, the genome organization in Drosophila appears to depend primarily on the partitioning of chromatin state domains. We discuss recent work suggesting a fundamental conserved role of chromatin state in building domain architecture, and we consider insights into genome organization from recent studies in Drosophila.