This article reviews the clinical features and neurochemical hypotheses of obsessive-compulsive disorder (OCD) with a focus on the serotonin system. In DSM-5, OCD was moved from the anxiety disorders to a new category of Obsessive-Compulsive and Related Disorders. OCD is a common, typically persistent disorder marked by intrusive and disturbing thoughts (obsessions) and repetitive behaviors (compulsions) that the person feels driven to perform. The preferential efficacy of serotonin reuptake inhibitors (SRIs) in OCD led to the so-called serotonin hypothesis. However, direct support for a role of serotonin in the pathophysiology (e.g., biomarkers in pharmacological challenge studies) of OCD remains elusive. A role of the glutamatergic system in OCD has been gaining traction based on imaging data, genomic studies and animal models of aberrant grooming behavior. These findings have spurred interest in testing the efficacy of medications that modulate glutamate function. A role of glutamate is compatible with circuit-based theories of OCD.