The purpose of this article is to review the systemic management options for patients with metastatic renal cancer. We reviewed the literature regarding systemic management of metastatic renal cancer. Treatment options of chemotherapy agents, immunotherapy, molecularly targeted agents, allogeneic stem cell transplantation, vaccines, and other manipulations of the immune system are discussed. No chemotherapy agent used alone or in combination has consistently produced responses to substantiate its routine use. Interleukin-2 (IL-2) and interferon-α (IFN-α) have shown response rates ranging from 10% to 20%. Some studies have shown that retinoids may enhance the antitumor activity of IFN-α. Molecularly targeted agents and angiogenic agents are being actively pursued and several studies are showing response rates above 30%. Although nonmyeloablative allogeneic stem cell transplantation shows some promising results, they also have limitations to its use. Therapy strategies that incorporate vaccines as part of comprehensive immune manipulations are also being studied. The systemic treatment of patients with advanced renal cell cancer continues to be a significant challenge. Immunotherapy treatment has shown response in up to 20% of patients. Unfortunately, most do not respond. The current technologies are promising and may be the key step for introduction of better treatments for renal cancer care.