Genome compaction is a universal feature of cells and has emerged as a global regulator of gene expression. Compaction is maintained by a multitude of architectural proteins, long non-coding RNAs (lncRNAs), and regulatory DNA. Each component comprises interlinked regulatory circuits that organize the genome in three-dimensional (3D) space to manage gene expression. In this review, we update the current state of 3D genome catalogues and focus on how recent technological advances in 3D genomics are leading to an enhanced understanding of disease mechanisms. We highlight the use of genome-wide chromatin conformation capture (Hi-C) coupled with oligonucleotide capture technology (capture Hi-C) to map interactions between gene promoters and distal regulatory elements such as enhancers that are enriched for disease variants from genome-wide association studies (GWASs). We discuss how aberrations in architectural units are associated with various pathological outcomes, and explore how recent advances in genome and epigenome editing show great promise for a systematic understanding of complex genetic disorders. Our growing understanding of 3D genome architecture-coupled with the ability to engineer changes in it-may create novel therapeutic opportunities.