Understanding how 3D genome structure varies between cell types, in development and disease, promises to enhance the interpretation of genome sequence and to accelerate the discovery of disease target genes. To explore 3D genome structure in different stages of development, we applied Genome Architecture Mapping in early mammalian development and in highly specialised cells of the brain). We found extensive cell-type specialisation of 3D chromatin contacts, and discovered large scale decondensation events, or ‘melting’, of long genes when most highly expressed. Through integration of 3D genome structure with single-cell expression and chromatin accessibility, we find cell-type specific hubs of contacts containing genes associated with specialised cellular functions, such as addiction and synaptic plasticity. Our recent work explores differences in 3D genome structure between the two copies of parental chromosomes, and the effects of environmental insults, such as addictive drugs or sleep deprivation on the complex 3D genome structures of brain cells, and their long-term impact in gene deregulation.