Interleukin (IL)-2 and IL-15 are two cytokine growth factors that regulate lymphocyte function and homeostasis. Early clinical interest in the use of IL-2 in the immunotherapy of renal cell carcinoma and malignant melanoma demonstrated the first efficacy for cytokine monotherapy in the treatment of neoplastic disease. Advances in our understanding of the cellular and molecular biology of IL-2 and its receptor complex have provided rationale to better utilize IL-2 to expand and activate immune effectors in patients with cancer. Exciting new developments in monoclonal antibodies recognizing tumor targets and tumor vaccines have provided new avenues to combine with IL-2 therapy in cancer patients. IL-15, initially thought to mediate similar biological effects as IL-2, has been shown to have unique properties in basic and pre-clinical studies that may be of benefit in the immunotherapy of cancer. This review first summarizes the differences between IL-2 and IL-15 and highlights that better understanding of normal physiology creates new ideas for the immunotherapy of cancer. The application of high, intermediate, and low/ultra low dose IL-2 therapy in clinical trials of cancer patients is discussed, along with new avenues for its use in neoplastic diseases. The growing basic and pre-clinical evidence demonstrating that IL-15 may be useful in immunotherapy approaches to cancer is also presented.