T-cell immunotherapy relies on the fundamental concept that tumor antigens exist and are presented in the context of MHC molecules for recognition by specific T cells capable of cytolysis. However, heterogeneous expression of most characterized tumor antigens limits the broad applicability of cancer vaccines that target such antigens. Telomerase, on the other hand, represents a prototype of a universal tumor antigen due to both its expression by the vast majority of tumors and its inherent functional involvement in oncogenic transformation. Given these attractive features, the identification of epitopes within human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, has led to the investigation of this tumor antigen as a broadly applicable immunological target. Basic immunological analyses have revealed that hTERT is immunogenic, and initial clinical trials of multiple vaccine formulations have demonstrated that hTERT-specific immune responses can be safely induced in patients and impact on clinical outcomes. Second-generation vaccines are now addressing strategies to enhance cellular immunity against hTERT without toxicity. Findings obtained from these trials will inform the possibility of broad-spectrum cancer immunotherapy or even immunoprevention.