Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancers, with high incidence rates in Eastern to Central Asia, along the Rift Valley in East Africa, and in South Africa. The causes of ESCC vary by region, with smoking and heavy alcohol consumption being well-established risk factors in some regions but not others. Other risk factors include polycyclic aromatic hydrocarbons, high-temperature foods, diet, oral health, and the microbiome. Genomic studies have identified several regions affecting susceptibility, but more research is needed, especially in high-incidence areas of Asia and Africa. ESCC has a poor prognosis due to late-stage diagnosis, and its etiology is complex, with varying risk factors across populations. Socioeconomic status (SES) is a consistent risk factor, and tobacco and alcohol consumption are significant contributors. Diet, particularly poor diet, may also play a role, but specific dietary agents have not been identified. Future research should focus on understanding the role of genetic factors and the microbiome in ESCC etiology, as well as improving research infrastructure in high-incidence countries.Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancers, with high incidence rates in Eastern to Central Asia, along the Rift Valley in East Africa, and in South Africa. The causes of ESCC vary by region, with smoking and heavy alcohol consumption being well-established risk factors in some regions but not others. Other risk factors include polycyclic aromatic hydrocarbons, high-temperature foods, diet, oral health, and the microbiome. Genomic studies have identified several regions affecting susceptibility, but more research is needed, especially in high-incidence areas of Asia and Africa. ESCC has a poor prognosis due to late-stage diagnosis, and its etiology is complex, with varying risk factors across populations. Socioeconomic status (SES) is a consistent risk factor, and tobacco and alcohol consumption are significant contributors. Diet, particularly poor diet, may also play a role, but specific dietary agents have not been identified. Future research should focus on understanding the role of genetic factors and the microbiome in ESCC etiology, as well as improving research infrastructure in high-incidence countries.