The startle reflex is a contraction of the skeletal and facial musculature in response to an intense sensory stimulus. While the 'primary' neural control of startle involves brain structures at, or below, the level of the mesencephalon, the startle reflex (SR) exhibits several forms of plasticity that are modulated by the forebrain. Sensorimotor gating of the SR occurs when the reflex is inhibited by a weak 'pre-pulse' that occurs 30-500 ms prior to the startling stimulus. Since 'pre-pulse inhibition' (PPI) of startle may be impaired in certain psychiatric and neurologic disorders (e.g. schizophrenia, schizotypal personality disorder and Huntington's disease), there has been considerable interest in determining the neural substrates of this form of startle plasticity. In rats, PPI is modulated by neural elements linking the limbic cortex with the striatum and pallidum. These substrates may include hippocampal glutamate efferents to the ventral striatum and striatal GABAergic efferents to the ventral pallidum. The striatal dopaminergic modulation of PPI appears to involve primarily D2, but not D1, receptors. Pallidal efferents may impinge directly on the 'primary' startle circuitry via projections to the mesencephalon or, indirectly, via projections to the thalamus. Evidence is reviewed for other neurochemical substrates of PPI-including acetylcholine and opiates. Sensorimotor gating of the startle reflex appears to have a discrete and identifiable set of neural substrates that may be important for our understanding of neuropsychiatric disorders characterized by deficient suppression or 'gating' of sensory, cognitive or motor processes.