The promyelocytic leukemia (PML) protein is a tumor suppressor acting as the organizer of nuclear matrix-associated structures named nuclear bodies (NBs). The involvement of PML in various cell processes, including cell death, senescence or antiviral defense underlines the multiple functions of PML due to its ability to interact with various partners either in the cytoplasm or in the nucleus. The importance of paracrine signaling in the regulation of PML expression is well established. More recently, a growing body of evidence also supports PML as a key regulator of cytokine signaling. These findings shed light on unsuspected biological functions of PML such as immune response, inflammation and cytokine-induced apoptosis. Here we review the current understanding of the pleiotropic activities of PML on cytokine-induced signaling.