Histone variants are important regulatory molecules in cancer. Vardabasso et al. have found that histone variant H2A.Z.2 is highly expressed in metastatic melanoma and is associated with poor prognosis. The authors found that H2A.Z.2-regulated genes — which are targets of the transcription factors E2F1 and E2F4 — are highly expressed cell cycle regulatory genes that acquire a unique signature of H2A.Z.2 occupancy in melanoma cells: H2A.Z.2 is enriched at the promoter region and depleted in the gene body. In addition. H2A.Z.2-regulated genes bind the bromodomain and extraterminal domain (BET) protein BRD2 — the levels of which are also elevated in melanoma samples — in a H2A.Z.2-dependent manner. Importantly, the authors reported that knocking down H2A.Z.2 sensitizes melanoma cells to BET and MEK inhibitors, which are potential therapies for melanoma.