In 1992, high-dose bolus interleukin (IL)-2 was granted Food and Drug Administration approval based on its ability to produce durable complete responses in a small number of patients with metastatic renal cell carcinoma (RCC). However, the substantial toxicity and limited efficacy that is associated with IL-2 has narrowed its application to highly selected patients treated at specialized centers. In recent years, the relative merits of low- and high-dose cytokine regimens have been clarified by the results of 4 randomized trials. Taken together, these studies suggest that high-dose IV bolus IL-2 is superior in terms of response rate and possibly response quality to regimens that involve either low-dose IL-2 and interferon-alpha, intermediate- or low-dose IL-2 alone, or low-dose interferon-alpha alone. More significantly, investigations associated with these trials suggest that the potential exists for identifying predictors of response (or resistance) and limiting IL-2 therapy to those most likely to benefit. The Cytokine Working Group has launched the high-dose IL-2 "select" trial to determine, in a prospective fashion, if the predictive model proposed by Atkins et al. can identify a group of patients with advanced RCC who are significantly more likely to respond to high dose IL-2-based therapy ("good" risk) than a historical, unselected patient population. For patients unlikely to benefit from IL-2, are unable to receive it or who progress after IL-2, the emergence of molecularly targeted therapies offers hope for improved clinical outcome. As the list of effective therapies for metastatic RCC grows, improvements in patient selection and more "targeted" approaches will be required to optimize the benefits of cytokine therapy in metastatic RCC.