IL-15 is an immune-enhancing cytokine belonging to the IL-2 family, which supports survival, proliferation and functional activities of NK, NK-T, T and B cells. Moreover, IL-15 may support the growth and survival of different lymphoid malignancies, suggesting that targeting of the IL-15/IL-15R system or its downstream signaling cascade may result in therapeutic effects, in these tumors. On the other hand, given its immune-enhancing activities IL-15 has been considered a good candidate for cancer immunotherapy. Indeed, IL-15 or IL-15 super agonists have shown anti-tumor activity in several animal tumor models either alone or combined with other immune-enhancing molecules. Therefore, clinical trials of IL-15 or IL-15 super-agonists are ongoing in different cancers. Here we will summarize the biological features of the IL-15/IL-15R system and discuss its duality in tumor biology and the potential applications of IL-15 agonists and antagonists in cancer.