Numerous animal and clinical studies have shown that injection of T lymphocytes from a major histocompatibility complex matched donor can cure subjects with chemotherapy-resistant hematological malignancies. This graft-versus-tumor effect, which represents the most conclusive evidence that the immune system can cure cancer in humans, is mediated primarily if not exclusively by T cells specific for host minor histocompatibility antigens. Since minor histocompatibility antigens are present on all tissues and organs, injection of unselected donor T cells also causes graft vs. host disease, which drastically limits the use and benefits of this treatment. Recent studies in mice have shown that adoptive transfer of primed T cells targeted to a single major histocompatibility complex class I restricted immunodominant minor histocompatibility antigen can eradicate leukemia cells without causing any toxicity to the host. We present the promises and caveats of this and other new approaches for adoptive T cell immunotherapy of cancer.