Obsessive-compulsive disorder (OCD) is associated with abnormalities in the cortico-striatal–thalamic–cortical (CSTC) circuitry, and may be associated with dysregulation of neurotransmitters within this network. The major neurotransmitters of the CSTC are serotonin, dopamine, glutamate and γ-aminobutyric acid (GABA. This chapter reviews evidence of the involvement of these neurotransmitters in OCD from pharmaocological, genetic, and imaging studies. yielding an integrated neurotransmitter model of OCD. It concludes that the neurotransmitter model of OCD involves dopaminergic and glutamatergic overactivity in frontostriatal pathways, along with diminished serotonergic and GABAergic neurotransmission in frontolimbic systems. These neurotransmitter imbalances may explain frontostriatal hyperactivity and impaired frontolimbic emotion regulation. Advancing our understanding of neurotransmitter abnormalities in OCD, and how abnormalities in different transmitter systems relate to one another, holds promise for the development of new pharmacotherapies.