Interleukin (IL)-15 belongs to the common gamma-dependent cytokine family, along with IL-2, IL-4, IL-7, IL-9, and IL-21. IL-15 is crucial for the homeostasis of Natural Killer (NK) and memory CD8 T cells, and to fight against cancer progression. However, dysregulations of IL-15 expression could occur and participate in the emergence of autoimmune inflammatory diseases as well as hematological malignancies. It is therefore important to understand the different modes of action of IL-15 to decrease its harmful action in pathology without affecting its beneficial effects in the immune system. In this review, we present the different approaches used by researchers to inhibit the action of IL-15, from most broad to the most selective. Indeed, it appears that it is important to selectively target the mode of action of the cytokine rather than the cytokine itself as they are involved in numerous biological processes.