Cancer immunotherapy represents a potential treatment approach through non-specific and specific enhancement of the immune responses. Adoptive cell therapy (ACT) is a potential modality of immunotherapy that depends on harvesting T cells from the tumor-bearing host, activating them in vitro and infusing them back to the same host. Several cytokines, in particular IL-2, IL-7 and IL-15, have been used to enhance survival T cells in vitro. Although effective, conditioning of T cells in vitro with these cytokines requires long-term culture which results in the loss of expression of their trafficking receptors mainly CD62L. It also results in exhaustion of the activated T cells and reduction in their functions upon adoptive transfer in vivo. Our recent studies and those of other groups showed that brief (3 days) conditioning of CD8+ T cells by IL-12 in vitro can result in enhancing function of tumor-reactive CD8+ T cells. Adoptive transfer of these IL-12-conditioned CD8+ T cells into tumor-bearing mice, preconditioned with cyclophosphamide, 1 day before ACT, induced tumor eradication that was associated with generation of tumor-specific memory response. In this review, we summarize studies that indicated to the superiority of IL-12 as a potential cytokine for conditioning T cells for ACT. In addition, we discuss some of the cellular and molecular mechanisms that govern how IL-12 programs CD8+ T cells to enhance their functionality especially in vitro and its implication in combination with other ACT modalities, opening a avenue for the clinical application of this cytokine. [ABSTRACT FROM AUTHOR]