Using a CRISPR-Cas9 screen approach focused on chromatin factors to identify epigenetic players in melanoma drug resistance, we identified the chromatin associated histone deacetylase SIRT6 as a regulator of resistance to the clinically relevant BRAFi (dabrafenib) and BRAFi+MEKi (dabrafenib+trametinib) combination 119. The gene discussed is SIRT6; the disease is melanoma.