The field of melanoma biology has experienced a remarkable surge in recent years, owing to progress which has ranged from the most basic laboratory/preclinical discoveries to clinical developments that have begun to transform the management and prognosis for at least certain melanoma patients. Among the key areas that have contributed to this progress are studies relating to signaling and transcriptional pathways that regulate control over differentiation and survival of the melanocyte lineage. The identification of recurring activating mutations in specific signaling factors (B-RAF, N-Ras, c-KIT), amplification of other melanoma oncogenes (MITF, NEDD9), and the crucial recognition that certain of these genomic events occur within melanomas arising with specific clinical features (eg mucosal or acral origin) have led to clear recognition that melanoma is indeed “many different diseases.” While the various subclasses of melanoma may share common features, such as profound invasive and metastatic propensity, it is also likely that sharply focused therapeutic strategies may exploit the functionally critical molecular engines, which distinguish these subclasses. Certain strategies focus upon the immunogenicity and striking clinical opportunities afforded by immune modulation, while others focus more directly on tumor-specific targeting. This issue brings together some of the leaders who have contributed significant insights from basic melanoma biology to progress in the clinic.