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Complexity in genome architecture determines how gene expression programs are established, maintained, and modified from early developmental stages to normal adult phenotypes. Large scale and hierarchical organization of the genome impacts various aspects of cell functions, ranging from X-chromosome inactivation, stem-cell fate determination to transcription, DNA replication, and cellular repair. While chromatin loops and topologically-associated domains represent a basic structural or fundamental unit of chromatin organization, spatio-temporal organization of the genome further creates a complex network of interacting genome patterns, forming chromosomal compartments and chromosome territories. The understanding of human diseases, including cancers, auto-immune disorders, Alzheimer's, and cardiovascular diseases, relies on the associated molecular and epigenetic mechanisms. There is a growing interest in the impact of three-dimensional chromatin folding upon the genome structure and function, which gives rise to the question “What's in the fold?” and is the main focus of this review. Here we discuss the principles determining the spatial and regulatory relationships between gene regulation and three-dimensional chromatin landscapes, and how changes in chromatin-folding could influence the outcome of genome function in healthy and disease states.