Prepulse inhibition (PPI) of the startle response is an important measure of information processing deficits and inhibitory failure in schizophrenia patients. PPI is especially useful because it occurs in the same lawful manner in all mammals, from humans to rodents, making it an ideal candidate for cross-species translational research. PPI deficits occur across the "schizophrenia spectrum" from schizophrenia patients to their clinically unaffected relatives. Parallel animal model and human brain imaging studies have demonstrated that PPI is modulated by cortico-striato-pallido-thalamic (and pontine) circuitry. This circuitry is also implicated in schizophrenia neuropathology and neurophysiology. The finding of PPI deficits in schizophrenia patients has been replicated by many groups, and these deficits correlate with measures of thought disorder and appear to be "normalized" by second generation antipsychotic (SGA) medications. Consistent pharmacological effects on PPI have been demonstrated; among these, dopamine agonists induce PPI deficits and (in animal models) these are reversed by first and SGA medications. PPI is also significantly heritable in humans and animals and can be used as a powerful endophenotype in studies of families of schizophrenia patients. Genomic regions, including the NRGL-ERBB4 complex with its glutamatergic influences, are strongly implicated in PPI deficits in schizophrenia. PPI continues to hold promise as an exciting translational cross-species measure that can be used to understand the pathophysiology and treatment of the schizophrenias via pharmacological, anatomic, and genetic studies.