The last few years have witnessed something of a renaissance in the field of cancer immunotherapy, relating largely to the clinical advances that have been associated with the development of monoclonal antibodies (mAbs) targeting the immune inhibitory coreceptors, such as CTLA-4. Subversion of these inhibitory checkpoints is a powerful mechanism by which tumors could evade host immune responses. Therapeutic advances are based on a more substantial understanding of the factors and regulatory cells restricting effective immune therapies that have been derived from the study of preclinical models of tumor initiation, growth, and metastasis in immunecompetent mice. 1, 2 Now, anti-CTLA-4 mAbs have been shown to prolong overall survival in patients with advanced melanoma. 3, 4 CTLA-4 is the archetypal immune regulatory checkpoint. CTLA-4 is expressed exclusively on T cells, and its ligands CD80 (B7. 1) and CD86 (B7. 2) are restricted largely to professional antigenpresenting cells, such as dendritic cells and monocytes. Functionally, anti-CTLA-4 primarily counteracts the costimulatory activity of CD28, which shares the same two ligands. The precise mechanisms underpinning the enhanced antitumor immunity demonstrated with anti-CTLA-4 antibodies remain somewhat controversial. In addition to its direct cell intrinsic function in dampening effector T cell (Teff) responses, CTLA-4 is highly expressed on regulatory T cells (Tregs). The engagement of the receptors on Tregs appears critical for maximal antitumor activity by anti-CTLA-4 mAbs. 5 Many possible combinatorial strategies based on ipilimumab and/or Treg are being investigated in preclinical models or in the clinic. 6 One interesting possibility is to combine anti-CTLA-4 with an agent that blocks another inhibitory molecule on Treg, such as receptor activator of NF-kB (RANK) ligand (RANKL). RANK signaling controls osteoclastogenesis and bone resorption and has been targeted to prevent bone metastasis in breast and prostate cancers. A humanized anti-RANKL antibody (denosumab) appears to be a more effective inhibitor of bone metastasis than other osteoclast-targeting drugs. 7, 8 Recently, RANKL expression on Treg has been shown to engage the RANK receptor on cancer cells and to promote metastasis. 9 Inhibitors of RANK signaling, such as anti-RANKL antibody denosumab, already used against osteoclast-mediated bone resorption, may block direct Treg-induced metastases of certain cancers. We describe a case of rapidly advancing metastatic melanoma with aggressive and symptomatic bone metastases requiring treatment with the anti-RANKL antibody denosumab for palliation, in a patient who was concomitantly treated with the anti-CTLA4 antibody ipilimumab.