Melanoma begins with benign nevi and progresses to radial growth phase (RGP) and to vertical growth phase [(VGP), metastatic phenotype]. The molecular changes associated with these transitions are not yet well defined. However, transcriptional regulation of some genes that are critical in melanoma progression is beginning to be elucidated. The first part of this review will focus on our recent studies demonstrating that progression of human melanoma is associated with loss of expression of the transcription factor AP-2. In metastatic melanoma cells, this loss resulted in overexpression of MCAM/MUC18 and MMP-2, and lack of expression of c-KIT. In further investigations, we inactivated AP-2 in SB-2 primary cutaneous melanoma cells by using a dominant-negative AP-2, the AP-2B gene. Expression of AP-2B in SB-2 cells augmented their tumorigenicity in nude mice and upregulated MMP-2 expression and activity. We have also recently demonstrated that loss of AP-2 expression in metastatic melanoma cells resulted in overproduction of the thrombin receptor, PAR-1. Other studies have shown that AP-2 regulates additional genes involved in melanoma development and progression, including E-cadherin, p21/WAF-1, HER2, Bcl-2, FAS/APO-1, IGF-R-1, and VEGF. We propose that loss of AP-2 is crucial in the development of malignant melanoma. Additionally, the transition of melanoma cells from RGP to VGP is associated with overexpression of two transcription factors, CREB and ATF-1, both of which may act as survival factors for human melanoma cells. The second part of the review will briefly discuss the role of other transcription factors, including ATF-2, SNAIL, MITF, and NFkappaB in the progression of human melanoma and will summarize recent knowledge on how changes in the expression of these transcription factors contribute to acquisition of the metastatic phenotype in human melanoma.