Starting in the late 1980s, cytokines were considered the mainstay of treatment for locally advanced or metastatic renal cell carcinoma (RCC) because of a lack of improved survival with either chemotherapy or hormonal therapy alone. The cytokine agents interferon alfa (IFNα) and interleukin-2 (IL-2) have been the most evaluated, but a low overall response rate and a marginal survival advantage, coupled with significant toxicity, make these therapies less than ideal. Although complete tumour responses have occasionally been seen with high-dose IL-2, this therapy is associated with significant morbidity and mortality, and its approval has been based on limited nonrandomized evidence. Newer anti-angiogenesis agents have been evaluated as single agents and in combination with INFα, and these are now considered the standard of care for most patients with RCC. However, cytokines may still occasionally be recommended when angiogenesis inhibitors are not available or are contraindicated. In the present paper, we discuss the evidence for the use of cytokine therapy in the setting of pre– and post–targeted therapy for RCC.