METCAM/MUC18, an integral membrane cell adhesion molecule (CAM) in the Ig-like gene super-family, is expressed in about nine normal cells/tissues. Since it has an immunoglobulin-like extra-cellular domain and a cytoplasmic domain, which contains five consensus sequences potentially to be phosphorylated by PKA, PKC, and CK2, METCAM/MUC18 is capable of performing typical functions of CAMs, such as mediating cell-cell and cell-extracellular interactions, crosstalk with intracellular signaling pathways, and modulating social behaviors of cells. Aberrant expression of METCAM/MUC18 alters cellular motility and invasiveness, changes cellular survival and growth, and affects the progression of tumor cells. For most cancer cell lines, increased expression of METCAM/MUC18 promotes the malignant progression of melanoma, prostate cancer, breast cancer, angiosarcoma and osteosarcoma, suggesting a promoter role in tumor progression. On the other hand, over-expression of METCAM/MUC18 suppresses the malignant progression of one mouse melanoma subline, human ovarian cancer cell lines, and perhaps cells of nasopharyngeal carcinoma and haemangioma, suggesting a suppressor role in tumor progression. In the light of this, the role of METCAM/MUC18 in the progression of different cancer types may be modulated by different intrinsic factors present in cancer cells derived from different tissues/organs, as well as by factors in the tumor stromal microenvironment. Many possible mechanisms mediated by this CAM during early tumor development and metastasis will be discussed.