The structure of neuronal circuits that subserve cognitive functions in the brain is shaped and refined throughout development and into adulthood. Evidence from human and animal studies suggests that the cellular and synaptic substrates of these circuits are atypical in neuropsychiatric disorders, indicating that altered structural plasticity may be an important part of the disease biology. Advances in genetics have redefined our understanding of neuropsychiatric disorders and have revealed a spectrum of risk factors that impact pathways known to influence structural plasticity. In this Review, we discuss the importance of recent genetic findings on the different mechanisms of structural plasticity and propose that these converge on shared pathways that can be targeted with novel therapeutics.