Schizophrenia psychopathology clusters around several symptom domains. One of these domains is negative symptomatology. We have defined the deficit syndrome as a disease entity characterized by the presence of primary enduring negative symptoms. A focus on primary negative symptoms demonstrates that deficit and nondeficit schizophrenia subgroups differ on clinical features, associated neuroimaging findings, neuropsychological and neurological measures, pattern of risk factors, and pharmacological response profiles. In the present article we focus on the importance of the distinction between primary and secondary negative symptoms for pathophysiology research. The development and mechanistic understanding of anti-negative symptom drugs may be informative regarding pathophysiology of primary negative symptoms. Although new antipsychotics are effective for secondary negative symptoms they have shown no efficacy for the deficit syndrome and new mechanisms of drug action appear to be required to address this aspect of the disease syndrome. The loss of precious human experiences and the association with poor long-term functional outcome justifies a focused and dedicated effort to discover the causes and treatments of this distinctive aspect of schizophrenia.