After discussing the role of the TNF-α/TNFR2 in tolerance, we then present and discuss the most recent developments that have led to the consideration of TNFR2 as a new brake to impede the anti-tumor immune response through its beneficial role on Tregs and the associated therapeutic perspectives for this molecule as a novel target for cancer immunotherapy. The gene discussed is TNFRSF1B; the disease is cancer.