This study identifies two highly recurrent mutations in the TERT promoter in human melanoma, found in 71% of cases, and also present in other cancers. The mutations, C228T and C250T, generate de novo ETS binding motifs and increase TERT promoter activity by 2-4 fold. These mutations were observed in 16% of 150 cancer cell lines, including bladder and hepatocellular cancers. The mutations are mutually exclusive and occur at a higher frequency than BRAF and NRAS mutations. They may contribute to melanoma development through TERT dysregulation and are likely early genetic events. The findings suggest that regulatory region mutations, in addition to coding sequences, may be important driver events in cancer. The study highlights the potential of telomerase inhibitors as a therapeutic approach. The results also indicate that promoter mutations may represent one of several mechanisms for TERT reactivation in cancer.This study identifies two highly recurrent mutations in the TERT promoter in human melanoma, found in 71% of cases, and also present in other cancers. The mutations, C228T and C250T, generate de novo ETS binding motifs and increase TERT promoter activity by 2-4 fold. These mutations were observed in 16% of 150 cancer cell lines, including bladder and hepatocellular cancers. The mutations are mutually exclusive and occur at a higher frequency than BRAF and NRAS mutations. They may contribute to melanoma development through TERT dysregulation and are likely early genetic events. The findings suggest that regulatory region mutations, in addition to coding sequences, may be important driver events in cancer. The study highlights the potential of telomerase inhibitors as a therapeutic approach. The results also indicate that promoter mutations may represent one of several mechanisms for TERT reactivation in cancer.