Studies have shown that adoptive transfer of ex vivo expanded tumor-infiltrating T lymphocytes (TIL) can mediate objective clinical responses in 50–70% of patients with advanced cancer. Due to practical limitations with TIL, we and others have genetically modified T cells to redirect their specificity to target cancer cells and viruses. Chimeric antigen receptors (CAR) were the first molecules used to redirect the specificity of T cells. CAR gene-modified T cells can target tumors in vitro and mediate tumor rejection in vivo in mice and humans. The second class of receptors used to redirect T cell specificity is the T cell receptor (TCR). Although not as thoroughly evaluated, TCR gene-modified T cells can also target tumors in vitro and mediate tumor rejection in vivo in mice and humans. This chapter discusses the development of CAR and TCR gene-modified T cells for use in treating cancer disease.