An alternative and novel approach that may improve glutamate NMDA receptor signaling and circuit connectivity in schizophrenia is to target the glutamate-NO-cyclic guanosine monophosphate (cGMP) signaling cascade. Nitric oxide is produced in the brain by a complex interaction with a functional glutamate NMDA receptor and there have been a number of clinical studies suggesting that signaling within the glutamate-NO-cGMP pathway may be disrupted in the illness (138, 181–187). As a gaseous signaling molecule, NO is classified as a neuromodulator or second messenger due to its ability to generate the production of cGMP. Nitric oxide-mediated signal transduction is an important driver for a variety of cellular processes throughout the body, including those critical for the establishment and maintenance of functional neuronal circuits and synaptogenesis (138, 188). In the cerebral cortex, neurons that produce NO are among the earliest differentiating cells that develop (138, 189). The presence of NO-producing neurons during critical developmental growth periods suggests that NO may be required for the formation and subsequent migration of neurons in the brain, and interruption of NO synthesis could lead to impairment in neuronal connectivity as is observed in schizophrenia.