Hepatocellular carcinoma (HCC) is a typically malignant tumor in the digestive system. The mortality of HCC ranks third place in the world, second only to lung cancer and colorectal cancer. For the characteristics of high invasiveness, high metastasis, high recurrence rate as well as short survival time, HCC treatment has always been difficult in clinical practice. Many causes have contributed to the appearance of these features, including insidious onset, high degree of malignancy, lack of effective early molecular diagnostic markers, and disease prediction models. The human chemokine-like factor superfamily (CMTMs) is a new gene family consisting of CKLF and CMTM1-CMTM8. CMTMs have a marvel domain which can activate and chemotaxis immune cells. Many studies have reported that CMTMs are involved in the regulation of cell growth and development, and play an important role in the malignant progression of the immune system and reproductive system, especially in the development of tumors. In this review, we summarized the structure and function of the human CMTMs, the relationship between its family members and HCC, the prognostic value, potential functions, and mechanisms in HCC. CMTMs could provide a new diagnostic and therapeutic target in clinical practice for patients with HCC.