The early appearance of monoamine systems in the developing mammalian CNS suggests that they play a role in neural development. We review data from two model systems that provide compelling new evidence of this role. In one model system – in utero exposure to cocaine – specific and robust alterations are seen in dopamine-rich areas of the cerebral cortex, such as the anterior cingulate cortex: D₁ receptor–G protein coupling is greatly reduced, the GABAergic system is altered and pyramidal dendrites undergo excessive growth. In a second model system – a transgenic mouse line in which the gene that encodes monoamine oxidase A (MAOA) is disrupted, resulting in excessively high 5-HT levels – barrels fail to form in the developing somatosensory cortex. Both models reveal the effects of very early manipulation of monoamines on forebrain development, and the long-term anomalies that persist into adulthood.