Molecular signatures of melanoma have propelled new approaches to early diagnosis, monitoring of treatment response, and targeted therapy. This review discusses messenger RNA (mRNA), genomic, and epigenomic melanoma biomarkers in blood and tissue specimens. The major focus is on tissue-based molecular assays to upstage sentinel lymph nodes (SLNs), and blood-based assays to detect melanoma progression by monitoring levels of circulating tumor cells (CTC) and circulating DNA. J. Surg. Oncol. 2011; 104:438–446. © 2011 Wiley-Liss, Inc.