Noncardiac chest pain (NCCP) is a common condition with significant morbidity and economic implications. Psychological factors, gastroesophageal reflux disease (GERD), alteration in pain perception, and esophageal dysmotility play an important role in the pathogenesis of the disorder. Proton pump inhibitor (PPI) therapy is the most effective medical intervention for the treatment of GERD-related NCCP, as well as the most cost-effective diagnostic strategy for this condition. Pain modulators such as tricyclic antidepressants, trazodone, and selective serotonin reuptake inhibitors infer a visceral analgesic effect and consequently are the treatment of choice for patients with non-GERD-related NCCP. Furthermore, cognitive behavioral therapy has also been shown to be useful in the management of subset of patients with non-GERD-related NCCP. Newer therapeutic modalities and interventions such as lower esophageal sphincter injection of botulinum toxin in NCCP patients with spastic esophageal motility disorders, theophylline, and 5-HT4 receptor agonists may supplement or replace current treatment for non-GERD-related NCCP. Future compounds may include new visceral analgesics or medications that interfere with the development of peripheral or central sensitization.