In vivo studies using cell‐derived xenograft and patient‐derived xenograft mouse models as well as a 4‐nitroquinoline 1‐oxide‐induced ESCC model in esophageal‐specific Rtn4ip1 knockout mice demonstrate the essential role of RTN4IP1 in ESCC development. This evidence concerns the gene RTN4IP1 and esophageal squamous cell carcinoma.