The crossing of nerve tracts from one hemisphere in the brain to the contralateral sense organ or limb is a common pattern throughout the CNS, which occurs at specialised bridging points called decussations or commissures. Evolutionary and teleological arguments suggest that midline crossing emerged in response to distinct physiological and anatomical constraints. Several genetic and developmental disorders involve crossing defects or mirror movements, including Kallmann's and Klippel-Feil syndrome, and further defects can also result from injury. Crossed pathways are also involved in recovery after CNS lesions and may allow for compensation for damaged areas. The development of decussation is under the control of a host of signalling molecules. Growing understanding of the molecular processes underlying the formation of these structures offers hope for new diagnostic and therapeutic interventions.