Non-cardiac chest pain (NCCP) is defined as recurring, angina-like, chest pain of non-cardiac origin. Studies have estimated that gastroesophageal reflux disease (GERD) is the most common contributing factor for NCCP. In patients with non-GERD related NCCP, esophageal motility disorders, and functional chest pain of presumed esophageal origin are the main underlying mechanisms for symptoms. Epidemiologic studies show a high prevalence of panic disorder, anxiety and major depression in NCCP patients. The diagnostic esophageal workup starts only after that cardiac and pulmonary diseases have been ruled out. NCCP patients with typical reflux symptoms are more likely to have GERD-related NCCP than those without typical reflux symptoms. High-dose proton pump inhibitor trial (PPI test) can be used to confirm the diagnosis of GERD-related NCCP. Negative upper endoscopy is quite common. For patients unresponsive to antireflux treatment and with negative endoscopy, impedance-pH monitoring should be done. Treatment of patients with non-GERD-related NCCP has focused on esophageal (hypercontractile or spastic) motility disorders and esophageal visceral hypersensitivity. In the first case, several trials using calcium channel blockers, nitrates, anticholinergics, or botulinum toxin injection and recent trials with endoscopic myotomy have been conducted. In case of visceral hypersensitivity, studies found that the amelioration, when compared to placebo, was significant with venlafaxine, sertraline, and imipramine. In this context, also cognitive behavioral therapy has been proposed.