This study identifies two highly recurrent mutations in the *TERT* promoter region of human melanoma, which are also observed in other cancer types. These mutations, C228T and C250T, generate de novo consensus ETS binding motifs and increase transcriptional activity from the *TERT* promoter by 2-4 folds. The mutations were found in 71% of melanomas and 16% of diverse cancer cell lines, with preliminary evidence of elevated frequency in bladder and hepatocellular cancers. The high prevalence and mutual exclusivity of these mutations suggest they may function as driver events contributing to oncogenesis through TERT dysregulation. This finding highlights the importance of regulatory region mutations in cancer development and supports the need for further research on telomerase inhibitors.This study identifies two highly recurrent mutations in the *TERT* promoter region of human melanoma, which are also observed in other cancer types. These mutations, C228T and C250T, generate de novo consensus ETS binding motifs and increase transcriptional activity from the *TERT* promoter by 2-4 folds. The mutations were found in 71% of melanomas and 16% of diverse cancer cell lines, with preliminary evidence of elevated frequency in bladder and hepatocellular cancers. The high prevalence and mutual exclusivity of these mutations suggest they may function as driver events contributing to oncogenesis through TERT dysregulation. This finding highlights the importance of regulatory region mutations in cancer development and supports the need for further research on telomerase inhibitors.