The tumorigenic and metastatic phenotype of melanoma cells correlates well with an increased expression of cell-cell and cell-matrix adhesion receptors. The human Mel-CAM gene encodes a transmembrane glycoprotein, also designated MCAM, MUC18 or CD146, that belongs to the immunoglobulin superfamily and functions as a Ca2+-independent cell adhesion molecule. The deduced human sequence of 603 amino acids consists of a signal peptide, five immunoglobulin-like domains, a transmembrane region and a short cytoplasmic tail. Mel-CAM expression is restricted to advanced primary and metastatic melanomas and to cell lines of the neuroectodermal lineage, but not normal melanocytes. Mel-CAM is found on 80% of advanced primary human mela-nomas and correlates well with development of metastatic disease. Mel-CAM activation initiates an outside-in signaling pathway that involves the protein tyrosine kinases Fyn, FAK and paxillin. Mel-CAM influences the dynamics of Actin cytoskeleton rearrangement and is essential for the maintenance of thymic architecture and function.