Persistent negative symptoms and cognitive dysfunction are a major cause of chronic disability in schizophrenia. Atypical antipsychotics such as clozapine, risperidone, and olanzapine induce significantly greater improvement in negative symptoms than that which is obtained with conventional agents. However, it remains unclear whether these agents treat core negative symptoms of schizophrenia, or simply induce less secondary psychopathology. A second approach for treatment of persistent negative symptoms is the use of N-methyl-D-aspartate (NMDA) receptor-stimulating agents, such as glycine, D-serine or D-cycloserine. These agents, when added to conventional or atypical antipsychotics, may induce significant additional reduction in both negative and cognitive symptoms.