A novel approach for cancer immunotherapy is to augment T-cell-mediated immunity by blocking inhibitory signals that suppress T-cell function. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a key negative regulator of T-cell activation. CTLA-4 blockade using anti-CTLA-4 monoclonal antibodies (mAbs) potentiates the T-cell response against tumors, and preliminary data on these agents demonstrate good efficacy and tolerability in the treatment of patients with metastatic melanoma and other cancers. This paper will review data from studies with anti-CTLA-4 mAbs to date, discuss some of the key clinical considerations emerging from early clinical trials with this therapeutic strategy, and provide an overview of ongoing and planned clinical trials for anti-CTLA-4 mAb therapy in metastatic melanoma and other cancers.