Cellular immunotherapies have immense potential as they can specifically target tumor antigens through native or artificial receptors. We have evaluated expanded T cells recognizing tumor antigens though their native receptor to target viruses such as EBV or HPV expressed on tumor cells with encouraging response rates when using either autologous cells or donor derived cells post transplant. More recent studies have infused closely matched third-party virus-specific T cells and reported encouraging response rates between 50 and 90%. As most tumors do not express viral antigens we have also evaluated tumor-associated antigens (TAAs) which are expressed by many malignancies but otherwise are found only in germline tissues that are immune privileged and therefore not susceptible to T-cell attack. We have used peptide libraries that can present both HLA-class I- and class II-restricted epitopes to reactivate TAA-specific T cells and to overcome the possibility of tumor escape by targeting multiple epitopes in 5 antigens in clinical trials in lymphoma, myeloma and acute leukemia. Clinical responses have been seen in all studies correlating with the detection of tumor-reactive T cells in patient peripheral blood post-infusion directed against both targeted antigens as well as non-targeted TAAs indicating antigen/epitope spreading. Chimeric antigen receptors may also be used to genetically modify T cells and strategies targeting CD19 are highly successful against B-cell non-Hodgkin lymphomas and acute lymphoblastic leukemia. The development of equivalent adoptive cell therapies (ACTs) that target malignancies of T-cell origin is a challenge due to shared expression of most targetable surface antigens between normal and malignant T cells, potentially leading to fratricide of CAR T cells or profound immunodeficiency. We are currently evaluating CD30 as a target expressed on only a subset of T cells and CD5.