Abstract Human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, is an attractive target antigen for cancer immunotherapy due to its expression in the vast majority of human tumors. The first immunogenic peptide described from hTERT was the HLA-A2–restricted peptide hTERT540 (ILAKFLHWL). However, much discrepancy exists about the processing and presentation of this epitope on the surface of neoplastic cells. Originally, it was described that specific CTL can be generated in vitro and that such cells are able to kill a range of hTERT+ tumor cell lines and primary tumors in a peptide-specific, HLA-A2–restricted fashion. Furthermore, it was described that vaccination of cancer patients with hTERT540 introduced functional antitumor CD8+ T cells in patients. More recently, it was described that most patients with cancer have circulating hTERT540-specific CD8+ T lymphocytes. In contrast, several other studies have concluded that hTERT540 is not presented on the surface of tumor cells and that immunization of cancer patients with hTERT540 leads to the introduction of specific T cells that do not recognize tumor cells in vivo. In the present commentary, we summarize these highly contradictive results about this potentially very important T-cell epitope. Furthermore, we describe novel data showing that naturally occurring immune responses against hTERT540 are, although rare, present in cancer patients and that such hTERT540-specific T cells are able to recognize and kill cancer cells. Hence, our data support the findings that hTERT540 peptide is presented by human tumors and can be a target for CTL-mediated tumor lysis.