Symptoms of schizophrenia cluster into distinct domains: positive symptoms (hallucinations, delusions, thought disorder), negative symptoms (anhedonia, thought paucity, alogia), and cognitive dysfunction (attention, working memory, and executive dysfunction). The pharmacologic strategies, genetics, and disease courses associated with these domains differ from one another. Therefore, it has been hypothesized that they are distinct disease entities or at least have distinct pathophysiologies. For this reason, a useful strategy for treatment development may be to investigate these different symptom domains individually for distinct and optimal treatments. Existing antipsychotic drugs act by blocking dopamine and serotonin receptors, primarily targeting positive symptoms. Cognitive dysfunction remains a distinct and potentially important clinical target. The National Institute of Mental Health took the lead in organizing a government/academic/industry cooperative initiative called Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) to isolate distinct cognitive disruptions, identify putative molecular targets active in modulating cognition, find actual drug candidates for those targets, and promote the development of a new treatments for schizophrenia (see F1). It is known that cognitive dysfunction in outpatient schizophrenia populations accounts for a great part of the residual psychosocial impairment standing in the way of these individuals finding homes, social networks, and employment. A treatment for cognitive dysfunction in these populations has great potential for a reduction of not only symptoms but also illness burden. So far, the MATRICS Initiative has identified 1) the areas of cognition that are specifically impaired in schizophrenia, 2) the most likely molecular targets involved, and 3) a cognitive battery that is sensitive and specific enough for broad use. As a next step, the NIMH will organize a cognitive testing network in clinical research settings to rigorously test new drugs for treatment of cognitive dysfunction. The goal is to find medications that will supplement current antipsychotic drugs by improving cognition in general or in specific subtypes and that can achieve recognition by the Food and Drug Administration (FDA) as indicated medications for this condition. While FDA recognition has not yet been fully realized, a road map to this goal is emerging. This road map may be a template for other innovative treatment development efforts.