Melanoma is considered as one of the most aggressive forms of skin cancer and treatment is unsuccessful due to development of resistance. The complexity and different genetic alterations of melanoma makes it difficult to target. Therefore, finding the right treatment combination, attacking several signaling pathways at the same time might improve patient survival. To understand melanoma progression and metastasis it is necessary to have insight into signaling pathways and their downstream effectors, such as p21 (WAF1/Cip1), a regulator of cell cycle progression. p21 is often deregulated in human cancers and has previously been shown to induce growth arrest/senescence. In the present study, we investigated the expression and regulation of p21 in a melanoma cell line panel consisting of 17 cell lines. We found a strong correlation between p21 mRNA and protein levels in all cell lines, except for the LOX cell line. We then correlated p21 expression levels against the progression of melanoma without detecting any obvious pattern. Furthermore, we detected a strong correlation between p21 expression levels and the p53 status in all of the cell lines. The correlation between p53 and p21 was also found after treating A375 and SKMEL28 with inhibitors against the MAPK- and cAMP-pathways. These latter results suggest that p21 is tightly controlled by the p53 tumor suppressor gene. However, p21 expression has also been shown to be regulated independently of p53. To address this, we investigated the expression of a number of transcription factors that previously have been reported to bind to the p21 promoter. When comparing these expression levels with p21 expression we did not find any obvious correlation, either positve or negative. The role of p53-independent transcriptional regulation of p21 is not fully understood and further studies needs to be carried out to disclose its role.