p21/ WAF1/ Cip1 (p21), a cyclin-dependent kinase inhibitor, may act as an antioncogene, but may also behave as a tumor promoting factor by inhibiting apoptosis. p21 is also a transcriptional regulator, exerting this activity independently of cyclin-dependent kinases. Increased p21 protein levels were found in a subset of melanomas. However, the mechanism(s) contributing to the tolerance of high p21 levels in melanoma cells remains unexplained. Here, we show that the p21 protein positively regulates the promoter of microphthalmia-associated transcription factor (MITF), a transcription factor which plays a central role in the expression of melanocyte-specific genes, lineage determination, and survival of melanoma cells. p21 activated the MITF promoter-reporter, occupied the promoter in vivo and cooperated with cAMP response element binding protein (CREB) in promoter activation. In addition, p21 knockdown by shRNA resulted in a decrease of MITF protein and promoter activity, and p21 protein levels correlated with MITF mRNA in most cell lines tested. As the p21 gene is a known transcriptional target of MITF, the reciprocal stimulation of transcription may constitute a positive-feedback loop reinforcing MITF expression in melanoma cells. Our results might help explain the tolerance of increased p21 levels found in some melanomas.