Persistent negative symptoms are a major cause of chronic disability in schizophrenia. The primary management approach for negative symptoms is use of atypical antipsychotics. Among atypical antipsychotics, clozapine produces the most robust reductions in negative symptoms. Lesser degrees of reduction are observed with risperidone and olanzapine. 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. Significant benefit of these agents has been observed in combination with both conventional and newer atypical antipsychotics. Whether or not these agents are effective in combination with clozapine remains an open question, and large scale multicenter clinical trials are ongoing.