Nonrandom chromosomal conformations, including promoter-enhancer loopings that bypass kilobases or megabases of linear genome, provide a crucial layer of transcriptional regulation and move vast amounts of non-coding sequence into the physical proximity of genes that are important for neurodevelopment, cognition and behaviour. Activity-regulated changes in the neuronal '3D genome' could govern transcriptional mechanisms associated with learning and plasticity, and loop-bound intergenic and intronic non-coding sequences have been implicated in psychiatric and adult-onset neurodegenerative disease. Recent studies have begun to clarify the roles of spatial genome organization in normal and abnormal cognition.