Renal cell carcinoma evokes an immune response, which investigators have attempted to augment by administering cytokines in doses above physiological levels. In 1992, high-dose (HD) bolus interleukin-2 (IL-2) received US Food and Drug Administration approval for metastatic renal cell carcinoma based on data that revealed durable responses in a small percentage of patients. However, this regimen is associated with significant toxicity and cost, which has limited its application to highly selected patients treated at specialised centres. Several investigators have evaluated regimens with lower doses of IL-2 in an attempt to decrease toxicity. Attempts were also made to improve treatment efficacy by adding interferon (IFN)-α followed by 5-fluorouracil to low-dose IL-2 regimens. These regimens were reported to produce response rates and survival comparable to HD IL-2 with much less toxicity, but possibly fewer durable responses. Based on positive preclinical data, other cytokines (e.g., IFN-γ, IL-12) have also been given to patients with metastatic renal cell carcinoma with limited success. This review examines the clinical trials that have described the efficacy and toxicity of IL-2 and other cytokines in patients with renal cancer, with a particular focus on the Phase III trials that have helped to define the proper use of these agents.