Interleukin-1 (IL-1) is a major “alarm” upstream pro-inflammatory cytokine that also affects immunity and hemopoiesis, by inducing cytokine cascades. In the tumor arena, IL-1 is produced by malignant or microenvironmental cells. As a pleiotropic cytokine, IL-1 is involved in tumorigenesis and tumor invasiveness, but also in the activation of anti-tumor immunity. In the tumor milieu, IL-1 represents a feasible candidate cytokine for modulation, in order to tilt the balance between inflammation and immunity towards favorable induction of anti-tumor responses. IL-1α and IL-1β are the major agonists of IL-1, while IL-1Ra is a physiological inhibitor of pre-formed IL-1. In their secreted form, IL-1α and IL-1β bind to the same receptors and induce the same biological functions. However, IL-1α and IL-1β differ in their compartmentalization within the producing cell or the microenvironment. IL-1β is only active in its secreted form and mediates inflammation, which promotes carcinogenesis, tumor invasiveness and immunosuppression. On the other hand, IL-1α is mainly cell-associated; in the context of tumors, host- and tumor cell-derived IL-1α stimulates antitumor immunity, rather than inflammation. Recent breakthroughs in inflammasome biology and IL-1β processing/secretion, have spurred the development of novel anti-IL-1 agents which are being used in clinical trials in patients with diverse diseases with inflammatory manifestations. IL-1Ra is already FDA-approved and has been shown to be safe and efficient in alleviating symptoms of rheumatoid arthritis. In experimental cancer, IL-1Ra attenuates tumor-mediated inflammation and invasiveness. Better understanding of the integrative role of IL-1α and IL-1β in the malignant process will enable the application of novel IL-1 modulation approaches at the bedside, in cancer patients with minimal residual disease (MRD), as an adjunct to conventional approaches to reduce the tumor burden.