Esophageal cancer-related gene 4 (ECRG4) plays key roles in various malignancies, including lung cancer, prostate cancer, esophageal cancer, and breast cancer, and has potential applications in the early diagnosis, prevention, treatment, and prognosis of cancer. However, the mechanisms underlying the role of ECRG4 in cancer remain elusive. An association between ECRG4 and proliferation, migration, cell cycle, apoptosis, methylation, and ubiquitination in cancer has been found. Additionally, some studies have investigated the regulatory mechanism of the relationship between ECRG4 and long non-coding RNAs, co-factors, and resistance to chemotherapy. Drugs that demethylate ECRG4 are in clinical use. Thus, further investigation of the mechanisms by which ECRG4 influences tumorigenesis, and its clinical significance, are needed. The present study outlines the current understanding of the functions of ECRG4 in cancer and discusses its potential value in cancer therapy.