Renal cell carcinoma (RCC) accounts for 4% of all new cancer cases in males and 3% in females in the US. Compared to other solid tumors, it does not respond to traditional management modalities, such as chemotherapy and radiation therapy. However, it appears to be an immune-responsive tumor and several immunotherapeutic strategies have been investigated in the management of RCC with variable degrees of success. Active immunotherapy refers mainly to the use of vaccines, while adoptive (passive) immunotherapy includes the use of autologous immune cells, allogeneic immune cells (stem cell transplantation, donor lymphocyte infusion), as well as antibody delivery. Cytokine delivery with IL-2 has resulted in long-term disease-free survival in a small proportion of patients with metastatic disease. The continuous understanding of the mechanisms that underlie the immune complex networks has led to the identification of key molecules that play a major role in the immune response process. A panel of immuno-modulatory compounds that target such molecules has been tested in the preclinical and clinical setting. At the post-genomic era, the development of novel biomarkers can contribute to more accurate patient selection, resulting in higher responses and less toxicity of immunotherapeutic approaches.