Allogeneic hematopoietic stem cell transplantation from a compatible donor has been utilized as adoptive immunotherapy in metastatic, cytokine-refractory renal cell carcinoma (RCC). Since the year 2000, several investigators have established that RCC is susceptible to a graft-versus-tumor effect: they reported that patients with renal cancer may have partial or complete disease responses, in the 20-40% range, after allogeneic transplantation following a reduced-intensity regimen. However, transplant-related mortality is still high in the 10-20% range, and responses are rarely durable. Experimental evidence suggests that donor-derived T cells and natural killer cells are the main mediators of the graft-versus-RCC effect upon allogeneic hematopoietic stem-cell transplantation. Isolation of CD8(+) cytotoxic T lymphocyte clones recognizing several target antigens of graft-versus-RCC effect (minor histocompatibility antigens on RCC cells; a peptide epitope derived from human endogenous retrovirus type E; the tumor-associated antigen encoded by the Wilms' tumor 1 gene) has increased our knowledge of the disease and has opened up the possibility of antigen-specific adoptive cell therapy. The introduction in the clinic of molecularly targeted agents that interfere with neoangiogenesis, both monoclonal antibodies and small tyrosine-kinase inhibitor molecules (e.g., sunitinib, sorafenib and bevacizumab), has decreased the use of allogeneic transplantation. Although not curative, novel targeted agents may be combined with allogeneic transplantation or with adoptive cell therapy in order to maximize the chances of cure.