While the combined use of targeted therapies (BRAF and/or MEK inhibition) [7–9] as well as immunotherapies (monoclonal antibodies directed at CTLA-4 and PD-1/PD-L1) have shown significantly improved outcomes for melanoma patients with advanced disease [10, 11], evidence implicating dysregulated epigenetic mechanisms in the pathogenesis of melanoma and other malignancies is also accumulating at a rapid pace [12, 13]. The gene discussed is CTLA4; the disease is melanoma.