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PURPOSE The extremely high incidence of esophageal cancer in certain rural areas of China has prompted significant intellectual curiosity and research efforts both in China and abroad. METHODS We summarize the research progress over the past several decades in high-risk areas (Linxian, Cixian, Shexian, and Yanting) based on literature research and our field trip (2012-2013). RESULTS Considerable progress in clarifying the environmental risk factors and pathogenesis of esophageal cancer in high-risk areas has been achieved over the past several decades. Epidemiologic evidence suggests that carcinogen exposure and nutritional deficiency, rather than smoking and drinking, may be the major risk factors for esophageal cancer in the Taihang Mountains region, where the incidence of esophageal cancer is among the highest in the world. Two genome-wide association studies have identified variants in PLCE1 at 10q23 that are significantly associated with esophageal cancer risk. Recent whole-exome studies have revealed a comprehensive mutation pattern, in which the C>T transition is the predominant mutation type. CONCLUSIONS Despite extensive research, the main causative factors that contribute to esophageal cancer in high-risk areas have not yet been elucidated. Challenges in this research area include determining the causative role of nitrosamine, identifying other potential carcinogens, and conducting fruitful international collaborative studies based on a multidisciplinary approach. Increased international collaboration will contribute to a better understanding of the etiology of esophageal cancer.