Targeting CTLA-4 represents a new type of immunotherapeutic approach, namely immune checkpoint inhibition. Blockade of CTLA-4 by ipilimumab was the first strategy to achieve a significant clinical benefit for late-stage melanoma patients in two phase 3 trials. These results fueled the notion of immunotherapy being the breakthrough strategy for oncology in 2013. Subsequently, many trials have been set up to test various immune checkpoint modulators in malignancies, not only in melanoma. In this review, recent new ideas about the mechanism of action of CTLA-4 blockade, its current and future therapeutic use, and the intensive search for biomarkers for response will be discussed. Immune checkpoint blockade, targeting CTLA-4 and/or PD-1/PD-L1, is currently the most promising systemic therapeutic approach to achieve long-lasting responses or even cure in many types of cancer, not just in patients with melanoma.