Building on significant advances in basic tumor immunology over the past decade, current translational efforts to develop novel antitumor T cell therapeutics continue to accelerate. Both passive T cell immunotherapy (e.g., adoptive T cell transfusions) and active immunotherapy (e.g., vaccination) may eventually become part of the arsenal to treat cancer. Successful approaches will need to repair host immunoincompetence in T cell function, circumvent immunosuppressive factors of the tumor microenvironment, and optimize target antigens with regard to clinical applicability, autoimmunity, and risk of antigen mutation. Here, we characterize two model systems for the ex vivo activation and expansion of human T lymphocytes and describe the potential for providing broadly applicable antitumor specificity by targeting universal tumor antigens. Polyclonal CD4+ T lymphocytes can be activated and expanded using anti-CD3 and anti-CD28 antibodies presented on magnetic beads, and CD8+T lymphocytes can be successfully expanded using a novel genetically engineered cell-based technology that presents anti-CD3 and anti-CD28 along with the costimulatory molecule CD137 (4-1BBL). As the prototypical and best-described universal tumor antigen, the human telomerase reverse transcriptase hTERT is vastly overexpressed in human tumors but absent in most normal tissues. Cytotoxic T lymphocytes (CTL) recognize peptides derived from hTERT and kill hTERT-positive tumor cells of multiple histologies. Phase I trials translating these discoveries to novel active and passive T cell therapies have been initiated, with an eye toward combining these strategies once safety is established.