Esophageal cancer causes over 380,000 deaths per year and ranks as the sixth leading cause of cancer death worldwide. Two primary cell types, squamous cell carcinoma and adenocarcinoma, account for most cases. Although the rates of esophageal adenocarcinoma have risen rapidly in the United States and elsewhere, ESCC still accounts for 80% of all esophageal cancer cases in the world. Many of these cases occur in high-risk areas with sharp geographic boundaries within China, Iran, a small region of South America, South Africa, and Kenya. Studies of ESSC in economically developed countries, such as the US, point to smoking tobacco, heavy alcohol drinking, poor diets deficient in fresh fruits and vegetables, and low socioeconomic status as the main etiologic factors. Other independent risk factors may include being male and being African-American. Smoking tobacco and heavy alcohol consumption do not explain the incidence rates in the high-risk regions because these habits are less common and less intensely practiced in these high-risk areas compared to the low risk area. Also, in highrisk areas the incidence rates are similar in men and women despite differences in the rates of tobacco smoking and alcohol drinking. Therefore, it is important to consider a wide range of etiologic factors to explain the high rates of cancer in these populations.