Key players on the immunosurveillance program, T cells are regulated by their surface receptors such as T-cell receptor (TCR), and costimulatory molecules, optimizing T-cell activation. Some of these costimulatory molecules, such as the cytotoxic T-lymphocyte antigen 4 (CTLA-4), induce inhibitory effects on T cells. By "inhibiting the inhibitor" CTLA-4-blocking monoclonal antibodies represent a novel class of weapons against cancers. To better understand the promising future and the limits of this immunotherapy, this review dissects the molecular inhibitory mechanisms induced by CTLA-4 in T cells.