Interleukin (IL)-21 is a class I cytokine with sequence homology to the IL-2 cytokine superfamily. IL-21 signals through a heterodimer of a unique IL-21 receptor and the common gamma-chain cytokine receptor. Preclinical murine models suggested strong antitumor activity of IL-21 in renal cell carcinoma, melanoma and other tumor models. IL-21 antitumor activity was superior to IL-2 in these tumor models. A Phase I clinical trial of IL-21 in humans with metastatic renal cell carcinoma or melanoma began in May 2004. Clinical regressions were observed in renal cell carcinoma. Preliminary immunological and clinical findings of patients receiving IL-21 will be reviewed.