Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer often affecting the elderly and immunosuppressed. A study identified a previously unknown polyomavirus, Merkel cell polyomavirus (MCV), in MCC tumors. Using digital transcriptome subtraction (DTS), researchers detected a fusion transcript between MCV T antigen and a human receptor tyrosine phosphatase. Sequencing revealed a 5387-base-pair MCV genome, found in 80% of MCC tumors but only 8% in control tissues. In six of eight MCV-positive MCCs, viral DNA was integrated into the tumor genome in a clonal pattern, suggesting MCV infection preceded tumor cell clonal expansion. MCV may contribute to MCC pathogenesis. Polyomaviruses, including MCV, are suspected in human cancers, though evidence is limited. MCV shares features with other polyomaviruses, including T antigen, VP1, VP2/3, and replication origin sequences. It is most closely related to the MuPyV subgroup and AGM LPyV. MCV has a high homology to viruses in the MuPyV subgroup and is more distantly related to known human polyomaviruses and SV40. MCV was detected in 80% of MCC tumors, with viral DNA integrated into the tumor genome in six cases. Southern blotting confirmed MCV integration in these tumors. MCV integration was found at the PTPRG locus on chromosome 3p14. MCV infection and integration occurred before clonal expansion of tumor cells. MCV may have parallels to high-risk HPV, which causes cervical cancer after viral episome disruption and integration into the cervical epithelial cell genome. The study validates the utility of DTS for discovering cryptic human viruses but highlights its limitations. DTS detected MCV in one of four sampled tumors, with MCV transcripts present at low copy numbers. Future searches for other transforming viruses should use DTS on multiple highly uniform samples sequenced to a depth of 200,000 transcripts or more. DTS is less useful for low-abundance viruses in autoimmune disorders or chronic infections. The study shows DTS is a promising method for identifying previously unknown human tumor viruses.Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer often affecting the elderly and immunosuppressed. A study identified a previously unknown polyomavirus, Merkel cell polyomavirus (MCV), in MCC tumors. Using digital transcriptome subtraction (DTS), researchers detected a fusion transcript between MCV T antigen and a human receptor tyrosine phosphatase. Sequencing revealed a 5387-base-pair MCV genome, found in 80% of MCC tumors but only 8% in control tissues. In six of eight MCV-positive MCCs, viral DNA was integrated into the tumor genome in a clonal pattern, suggesting MCV infection preceded tumor cell clonal expansion. MCV may contribute to MCC pathogenesis. Polyomaviruses, including MCV, are suspected in human cancers, though evidence is limited. MCV shares features with other polyomaviruses, including T antigen, VP1, VP2/3, and replication origin sequences. It is most closely related to the MuPyV subgroup and AGM LPyV. MCV has a high homology to viruses in the MuPyV subgroup and is more distantly related to known human polyomaviruses and SV40. MCV was detected in 80% of MCC tumors, with viral DNA integrated into the tumor genome in six cases. Southern blotting confirmed MCV integration in these tumors. MCV integration was found at the PTPRG locus on chromosome 3p14. MCV infection and integration occurred before clonal expansion of tumor cells. MCV may have parallels to high-risk HPV, which causes cervical cancer after viral episome disruption and integration into the cervical epithelial cell genome. The study validates the utility of DTS for discovering cryptic human viruses but highlights its limitations. DTS detected MCV in one of four sampled tumors, with MCV transcripts present at low copy numbers. Future searches for other transforming viruses should use DTS on multiple highly uniform samples sequenced to a depth of 200,000 transcripts or more. DTS is less useful for low-abundance viruses in autoimmune disorders or chronic infections. The study shows DTS is a promising method for identifying previously unknown human tumor viruses.