A comprehensive genomic analysis of 164 oesophageal carcinomas from Western and Eastern populations revealed distinct molecular features between oesophageal squamous cell carcinomas (ESCCs) and oesophageal adenocarcinomas (EACs). ESCCs showed molecular similarities to squamous cell carcinomas of other organs, while EACs resembled gastric adenocarcinomas. Three molecular subclasses of ESCCs were identified, but none showed evidence of human papillomavirus involvement. ESCCs frequently had genomic amplifications of CCND1, SOX2, and TP63, whereas EACs showed more amplifications of ERBB2, VEGFA, and GATA4/GATA6. EACs were closely related to chromosomally unstable gastric adenocarcinomas, suggesting they may be considered a single disease entity. However, some molecular features, such as DNA hypermethylation, were more common in EACs. These findings provide a framework for better classification of these tumours and potential new therapies. Oesophageal cancers have low survival rates, with 12–20% 5-year survival in Western populations. ESCCs are more common in the upper and mid-oesophagus and are associated with smoking and alcohol, while EACs are more common in the lower oesophagus near the gastric junction and are linked to obesity, reflux, and Barrett's oesophagus. The classification of EAC and ESCC remains unresolved, and there is debate about the utility of histological distinctions. A comprehensive molecular analysis of 164 oesophageal tumours, 359 gastric adenocarcinomas, and 36 GEJ adenocarcinomas was conducted to improve classification. The study identified three molecular subtypes of ESCCs: ESCC1, ESCC2, and ESCC3. ESCC1 showed alterations in the NRF2 pathway, which is involved in oxidative stress response. ESCC2 had higher rates of mutations in NOTCH1 or ZNF750 and more frequent inactivating alterations of KDM6A and KDM2D. ESCC3 showed no evidence of cell cycle deregulation and had TP53 mutations in only one of four samples. ESCC subtypes showed geographic associations, with Vietnamese patients more likely to have ESCC1 and Eastern European/South American patients more likely to have ESCC2. EACs showed enrichment of C>A substitutions and APOBEC signatures, suggesting a role for tobacco chewing. EACs were closely related to chromosomally unstable gastric cancers, but differences in molecular features between EACs and gastric cancers were observed. These findings suggest that EACs and ESCCs are distinct diseases with different molecular characteristics and may require separate therapeutic approaches. The study highlights the importance of molecular classification in understanding and treating oesophageal cancers.A comprehensive genomic analysis of 164 oesophageal carcinomas from Western and Eastern populations revealed distinct molecular features between oesophageal squamous cell carcinomas (ESCCs) and oesophageal adenocarcinomas (EACs). ESCCs showed molecular similarities to squamous cell carcinomas of other organs, while EACs resembled gastric adenocarcinomas. Three molecular subclasses of ESCCs were identified, but none showed evidence of human papillomavirus involvement. ESCCs frequently had genomic amplifications of CCND1, SOX2, and TP63, whereas EACs showed more amplifications of ERBB2, VEGFA, and GATA4/GATA6. EACs were closely related to chromosomally unstable gastric adenocarcinomas, suggesting they may be considered a single disease entity. However, some molecular features, such as DNA hypermethylation, were more common in EACs. These findings provide a framework for better classification of these tumours and potential new therapies. Oesophageal cancers have low survival rates, with 12–20% 5-year survival in Western populations. ESCCs are more common in the upper and mid-oesophagus and are associated with smoking and alcohol, while EACs are more common in the lower oesophagus near the gastric junction and are linked to obesity, reflux, and Barrett's oesophagus. The classification of EAC and ESCC remains unresolved, and there is debate about the utility of histological distinctions. A comprehensive molecular analysis of 164 oesophageal tumours, 359 gastric adenocarcinomas, and 36 GEJ adenocarcinomas was conducted to improve classification. The study identified three molecular subtypes of ESCCs: ESCC1, ESCC2, and ESCC3. ESCC1 showed alterations in the NRF2 pathway, which is involved in oxidative stress response. ESCC2 had higher rates of mutations in NOTCH1 or ZNF750 and more frequent inactivating alterations of KDM6A and KDM2D. ESCC3 showed no evidence of cell cycle deregulation and had TP53 mutations in only one of four samples. ESCC subtypes showed geographic associations, with Vietnamese patients more likely to have ESCC1 and Eastern European/South American patients more likely to have ESCC2. EACs showed enrichment of C>A substitutions and APOBEC signatures, suggesting a role for tobacco chewing. EACs were closely related to chromosomally unstable gastric cancers, but differences in molecular features between EACs and gastric cancers were observed. These findings suggest that EACs and ESCCs are distinct diseases with different molecular characteristics and may require separate therapeutic approaches. The study highlights the importance of molecular classification in understanding and treating oesophageal cancers.