Treatment options for schizophrenia that address all symptom categories (positive, negative, and cognitive) are lacking. Novel compounds that regulate signaling by the major excitatory neurotransmitter in the brain, glutamate, are emerging as a novel approach for the treatment of this disorder. Currently available medications ameliorate positive symptoms but do not have efficacy in reducing negative symptoms or cognitive disturbances. It is possible that agents that target glutamatergic signaling in the CNS could have efficacy in reducing all major symptom clusters, providing a more comprehensive treatment strategy, and also avoiding some of the adverse effects that are seen with currently available treatments. Three major approaches for targeting glutamate signaling are now advancing in preclinical and clinical development. First are inhibitors for a transporter for glycine termed GlyT1. Glycine is a co-agonist with glutamate for a specific subtype of glutamate receptor, termed the NMDA receptor, which is thought to be critically involved in brain circuits that are disrupted in schizophrenia patients. Inhibiting GlyT1 increases glycine levels and can selectively increase NMDA receptor signaling. Another promising approach is to increase activity of another family of glutamate receptors, termed metabotropic glutamate receptors (mGlus), which play important modulatory roles in brain circuits that are thought to be disrupted in schizophrenia patients. Activation of the group I (mGlu5) and the group II (mGlu2 and mGlu3) mGlus is hypothesized to normalize the disruption of aberrant signaling in these circuits. Novel drug-like molecules that increase activity of these receptors have robust efficacy in animal models that predict efficacy in treatment of schizophrenia. Early clinical studies provide some support for potential utility of these targets in reducing symptoms in schizophrenia patients. Clinical studies that are underway will provide further insights into the potential utility of these compounds in the treatment of multiple symptom domains in schizophrenia patients.