The cell surface glycoprotein MUC18, a member of the immunoglobulin superfamily and homologous to several cell adhesion molecules, is associated with tumor progression and the development of metastasis in human malignant melanoma. Immunohistochemical and Northern blot analysis revealed that expression of the antigen is restricted to advanced primary and metastatic melanomas and to cell lines of the neuroectodermal lineage. The genomic sequence encoding the cell surface antigen spans approximately 14 kb and consists of 16 exons. The organization of the gene, which is related to that of the neural cell adhesion molecule N-CAM, shows a structure where each immunoglobulin-related domain is encoded by more than one exon. Sequencing of the putative MUC18 promoter region revealed a G + C-rich promoter lacking conventional TATA and CAAT boxes. Several motifs for binding of transcription factor Sp1 are present in the regulatory region, and only a single transcription start site within a presumed initiator sequence was identified. Sequence elements which might confer melanocyte-specific expression were not detected. Instead, recognition sequences for the transcription factors CREB, AP-2, and c-Myb, as well as CArG-box motifs, were observed. These elements may contribute to the differential regulation of the MUC18 gene in normal and malignant tissues and suggest a role for this putative adhesion molecule in neural crest cells during embryonic development.