Melanoma cell adhesion molecule (MCAM) is upregulated during melanoma progression, and associated with invasion and metastasis. Little is known about the factors that regulate MCAM expression in vivo. Mutations that upregulate MCAM have not been found, and AKT activating mutations are rare in melanomas. This suggests that an epigenetic factor may be responsible for upregulating MCAM and activating AKT in vivo. Although endothelin-1 and endothelin-3 (ET-1, ET-3) are physiologically relevant factors capable of upregulating MCAM in melanocytic cells, a mechanism of action has never been established. Here we show that pharmacologic inhibition of map kinase kinase (MEK) or phosphoinositol 3 kinase (PI3K) blocks MCAM upregulation by ET-3, implicating MEK and PI3K/Akt kinases in ET-3 regulation of MCAM. Despite the fact that there are cAMP response element binding protein (CREB) sites in the MCAM promoter, suppression of CREB expression by siRNA silencing does not block ET-3 mediated upregulation of MCAM. Rather, ET-3 stimulation of melanocytes promotes Akt phosphorylation at Ser 473, which is suppressed by PI3K inhibition or silencing of Akt, in turn blocking ET-3 upregulation of MCAM. We conclude therefore that ETs upregulate MCAM in an Akt and ERK/MEK-dependent, but CREB-independent manner, providing an understanding for possible pharmacologic intervention in progressing melanoma.