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The rules that dictate spatial and temporal organization of genomes are rapidly being elucidated through advances in the molecular manipulation of genomes, methods to measure proximity and dynamics in the cell nucleus, single cell measurements, microscopic imaging, biophysical principles and computational modeling. This hierarchical organization can be viewed at many scales, all of which are dynamically altered to regulate transcription, replication, genome integrity and the changes in epigenetic states that define different cell types. Increasingly, we find evidence for causal linkages between alterations in 3D genome organization and disease. The 2019 conference on Genome Architecture in Cell Fate and Disease “The Eukaryotic Genome in 4 Dimensions: Integrative Approaches to Bridging Genotype and Phenotype” is the third meeting of its kind and will seek to promote interdisciplinary discussion of the most cutting edge principles in this field, including the latest technologies and concepts, relationships to chromosome function including development, disease, genome integrity and epigenetic inheritance.