Gastroesophageal reflux disease (GERD) is a common chronic disorder that is associated with a huge economic burden in the western countries and significantly decreased quality of life. This review focuses on the various multicultural issues in the epidemiology, pathophysiology, diagnosis, and treatment of GERD. The prevalence of GERD appears to be highest in North America and Europe, whereas epidemiologic data from the Indian subcontinent, Africa, South America, and the Middle East are sparse. A limited number of studies have elucidated ethnic differences in GERD in multiracial populations. African Americans and Asians appear to be at a lower risk for the development of complicated GERD including Barrett's esophagus (BE). Whether the pathophysiology of GERD differs among different populations remains to be answered satisfactorily. It appears that most of the factors involved in the pathogenesis of GERD, as described in western populations, are present in Asians but at a lower scale. The current recommendations for the management of GERD by the American College of Gastroenterology may not meet the need for different ethnic groups or for different geographic regions. Recognition of language barriers in understanding the common terms used to describe reflux symptoms should be borne in mind while treating GERD patients with different ethnic backgrounds. In addition, a universally accepted definition for treatment success in GERD patients is lacking. Given the negative impact on health-related quality of life, significant cost ramifications, and increased risk for BE and esophageal adenocarcinoma, the study of multicultural issues in GERD should be considered.