Adaptive immune responses appear to influence the natural history of cancer progression, as well as therapeutic outcomes, in cancer patients. However, accumulating evidence suggests resistance mechanisms exploited by tumors may play a dominant role in limiting the effectiveness of T cell-mediated cancer therapies. Inhibitory coreceptors expressed by T lymphocytes, or so-called immune checkpoints, are now recognized to play critical roles in regulating the termination of adaptive immune responses. An overview of early-phase trial results distinguish blocking antibodies targeting inhibitory coreceptors as a highly promising approach to cancer immunotherapy for patients with advanced clear cell renal cell carcinoma. Prospects for advanced-phase clinical testing and novel therapy combinations with immune checkpoint blocking agents are discussed.