SOX-9 was originally identified as a master regulator gene that plays a role in the differentiation of mesenchymal cells to chondrocytes. Since then, SOX-9 has been implicated in neural crest development and has emerged as a transcriptional regulator of melanogenesis. Because the role of immunohistochemical detection of SOX-9 in the routine diagnosis of melanoma has not been previously described, we attempted to elucidate the spectrum and labeling characteristics of this antibody in a large cohort of patients with metastatic melanoma. We analyzed the expression of SOX-9 on sections of metastatic melanoma in a tissue microarray and compared the expression of this marker with 3 commonly used melanocytic markers (MART-1, HMB-45 antigen, and S-100 protein). SOX-9 expression was noted in 52 of the 62 cases (83.9%). In comparison, HMB-45 was positive in 53 of the 62 cases (85.5%), MART-1 was positive in 59 of the 62 cases (95.1%), and S-100 protein was positive in 57 of the 62 cases (95%). Interestingly, there were 5 tumors that were negative for 2 or more markers while being positive for SOX-9. Furthermore, 3 of these were negative for all markers except for SOX-9. Our study illustrates that SOX-9 is expressed in a high percentage of melanomas. Furthermore, SOX-9 may be a useful adjunct in the work-up of metastatic melanoma, in such cases where the tumor is negative for the other commonly used melanocytic markers. Last, our data confirm that SOX-9 is not a specific marker for tumors of cartilage lineage and may be expressed in other tumors of neural crest origin.