Although valuable antischizophrenic drugs exist, they only partially ameliorate symptoms and elicit substantial side effects. Classic neuroleptic drugs act by blocking dopamine receptors. They can relieve some symptoms but not behavioral withdrawal features that are designated “negative” symptoms. Clozapine and related newer atypical neuroleptics may be more efficacious in relieving negative symptoms. Understandng their actions may facilitate new drug discovery. Agents influencing glutamate neurotransmission and N-methyl-d-aspartate receptors, especially the cotransmitter d-serine, are promising. Stimulation of the α7 subtype of nicotinic acetylcholine receptor may also be efficacious. The search for genes linked to schizophrenia has revealed several leads that may permit development of novel therapeutic agents. Promising genes include disrupted-in-schizophrenia-1, dysbindin, and neuregulin.